Chapter 30 Immunobiologics (2024)

KEY TERMS AND DEFINITIONS

• Passive immunity comes from the transfer of antibodies into an individual.

• Active immunity is a result of the body’s own production of antibodies after encountering recognized threats (e.g., antigens).

• Innate immunity refers to nonspecific protection against pathogens that is natural to humans from birth, such as the body’s external barriers to disease (eg, skin).

• Acquired immunity develops only after exposure to a specific recognized threat (eg, antigen).

LEARNING OBJECTIVES

After completing this chapter, you should be able to:

1. Recall discussed components of the immune system and classify types of immunity.

2. Recognize different types of immunizations.

3. Explain the value of disease prevention to public health and provide examples of how pharmacy personnel can support public health initiatives.

4. Interpret the CDC vaccination schedule for children and adults.

5. Recall the indications for immunosuppression and identify agents used for such purposes.

6. Define biosimilars and outline the purposes of such products.

The Immune System

Humans are born with a full immune system composed of cells, glands, organs, and fluids located throughout the body to fight invading pathogens (disease-causing organisms). An important step in this fight includes the initial recognition of toxins or invading organisms that enter the body, and our immune system is able to identify specific structures on these invaders known as antigens to perceive them as foreign entities. The immune system is further equipped with several specific and nonspecific means to fight such threats upon recognition. One specific defense is the production of substances called antibodies—molecules targeted against specific recognized antigens. A healthy immune system can produce immense quantities of antibodies to defend against specific attacks every day. Many antibodies disappear once they have helped to destroy the invading antigens, but some cells involved in antibody production remain and become memory cells. Memory cells retain the ability to produce a forceful and rapid antibody response if they encounter the antigen again, even after many years. Antibody-based protection from disease by the body’s defense system is a form of immunity.

The lymphatic system, which contains the main organs of immunity (called lymphoid organs)—including bone marrow, lymph nodes, the spleen, the thymus gland, and tonsils—is the part of the circulatory system that cleanses body fluids of foreign material as well as old or damaged cells. The fluid contained in this system is known as lymph. White blood cells (WBCs, described in detail in Chapter 25) important to the functioning of the immune system partially reside within lymph and are broken up into several categories of cells. They include the monocytes, eosinophils, basophils, leukocytes, and lymphocytes. Each type has a unique role in helping to protect the body. Lymphocytes develop in either the bone marrow (B-cells) or the thymus (T-cells) before circulating throughout the body. They are named based on where they develop, and each major type of lymphocyte (T-cell and B-cell) helps to provide the body with its ability to respond to immediate insults as well as develop specific immunity in response to recognized threats.

Vaccines and Immunization

Acquired immunity was recognized by people long before the immune system was understood or the agents that caused infection were known. It was noticed that some diseases, like measles or mumps, were often contracted after exposure to someone else who had these illnesses. It was also noted that some individuals who had contracted and recovered from certain communicable diseases did not get them again, even when they had close contact with patients who had the active disease. In the late 18th century, British physician Edward Jenner attempted to take advantage of these observations by exposing several children, including his own, to pus taken from a person with cowpox (a mild disease then common in milkmaids). This process made them immune to smallpox, one of the most widespread and deadly communicable diseases of the time. Jenner, through this therapy, was causing his patients’ bodies to produce antibodies against smallpox, which afforded them invaluable protection against such a formidable infection. Vacca is the Latin word for cow, so Jenner called his process vaccination.1 At the time, it was a revolutionary concept, and it ultimately proved to be a successful way to confer more consistent immunity in a way that is safer than direct pathogen exposure. The medical community has since refined the process to confer immunity without making the individual ill. Now commonly called immunization, this therapeutic strategy has worked to eliminate countless fatalities from communicable diseases such as smallpox, poliomyelitis, measles, mumps, rubella, tetanus, diphtheria, pertussis, influenza, pneumonia, hepatitis, and dozens of other threats to humanity.

Despite the availability of vaccines, pneumococcal pneumonia and influenza still result in tens of thousands of deaths each year in the United States among unvaccinated patients. Hepatitis A and B, also preventable by vaccine, cause many additional preventable illnesses and fatalities.2 It is the responsibility of all healthcare professionals to communicate accurate information related to immunizations to deter the spread of such preventable disease.

Because immunization programs have been very effective in countries like the United States, many people are not familiar with the deadly diseases that have been curtailed by childhood immunizations. Current generations are fortunate to not intimately know the damage that comes from smallpox, polio, or measles infections; this is almost entirely due to successful vaccination programs. In the face of the COVID-19 pandemic, being champions of correct information pertaining to the vaccination process, as well as those immunizations available to offer protection against COVID-19, is an important responsibility of all pharmacy personnel and healthcare professionals.

Vaccines can be separated into several categories based on how they are developed. Certain vaccines contain intact, but weakened, pathogens and are designated as live-attenuated. This type is the most likely to result in lifelong immunity after a single dose. While such vaccines are incapable of producing an infection in individuals with an intact immune system, immunosuppressed persons should not receive a live-attenuated vaccine without first speaking with their healthcare provider as their immune systems may not be healthy enough to tolerate them. Another category of vaccines contains killed pathogens: these are called inactivated. Additional categories of immunizations utilize components of the pathogen to trigger an immune response and may be referred to as recombinant, conjugate, subunit, or polysaccharide, depending on the specific part or parts of pathogen(s) used to create the vaccine. Nonlive vaccines are often administered as multiple doses to be sure that they confer long-term immunity. Some of these vaccinations also require doses provided at prescribed intervals long after an initial immunization, called boosters, to “remind” the immune system by stimulating the production of additional memory cells when the immune response may wane. Examples of inactivated immunizations include the vaccine against hepatitis B virus (HBV), which is composed of only the surface proteins of the virus, as well as the vaccine against human papillomavirus (HPV) which is made from the viral protein coat.

Other types of vaccines include those that utilize messenger RNA (mRNA) or an adenovirus vector. mRNA is constantly made by cells throughout the body, and it functions as a blueprint for the creation of many kinds of proteins that allow our bodies to function normally. Therefore, vaccines that utilize mRNA deliver specific instructions to the body’s cells so that our cells can manufacture a harmless antigen, which is then recognized by the immune system to produce memory cells in the process described above. The mRNA utilized by these vaccines cannot enter the nucleus of cells, which is where DNA is kept, and the mRNA used by the vaccine is destroyed by the cell after it is used to produce the harmless antigen. For these reasons, it is impossible for mRNA vaccines to affect or interact with our DNA. Adenovirus vector vaccines utilize a harmless nonpathogenic virus, which enters our cells and uses the body’s natural cellular machinery to produce an antigenic substance. This substance is then recognized by the body’s immune system to generate a memory cell-based immune response. The components of adenovirus vector vaccines are also incapable of integrating with the DNA found within our cells. Regardless of vaccine type, each product works to confer active immunity without risking the significant harm that may come from exposure to the pathogen in question. Several vaccines against infectious diseases are listed in Medication Table 30-1 (Medication Tables are located at the end of the chapter).

Vaccines have been developed for the prevention of many common and deadly infectious diseases, but there are currently no vaccines for some infections due to the ability of certain viruses to quickly change their antigens. Such change would make the memory cells developed by a vaccine unable to produce antibodies against the changed antigens. Currently, human immunodeficiency virus (HIV), hepatitis C, and the common cold do not have vaccines. Research is progressing, though, related to novel vaccine development for both infectious and certain noninfectious disease states.

Certain bacteria damage the body by producing dangerous products known as toxins. Antibodies against these toxins, however, may eliminate their harmful actions and prevent disease. To stimulate the production of these antibodies, immunization against toxin-producing organisms utilizes a vaccine that contains a harmless version of the toxin, known as a toxoid, thus stimulating the adaptive immune system. Examples of toxoid-containing vaccines are those against diphtheria and tetanus. Such products are listed in Medication Table 30-1, and combined immunizations (ie, single products that contain multiple antigens to stimulate active immunity against multiple pathogens) are presented in Medication Table 30-2.

Immunizations are administered via a variety of routes depending on the preparation used and/or the type of vaccine. The most common routes of administration have historically been by injection: subcutaneous (SUBQ), intradermal, or intramuscular (IM). Most vaccines are given by injection because they may not be well absorbed from the gastrointestinal tract. Rotavirus, cholera, and some typhoid vaccines, however, are given orally in order to produce localized immunity in the bowel; this is the point of entry for these agents in actual infection. Additionally, live-attenuated influenza vaccine has been produced as a nasal spray that is absorbed through the nasal mucosa.

Some immunizations can be administered at the same time as others (some are even mixed together as combination products, such as those described in Medication Table 30-2), while others must be separated by intervals of several weeks. The Centers for Disease Control and Prevention (CDC) publishes annual schedules of recommended vaccinations to prevent diseases for children and adults in the United States (Schedule 30-1 and Schedule 30-2, respectively). The CDC receives recommendations pertaining to vaccinations from a group of experts in the fields of medicine and public health known as the Advisory Committee on Immunization Practices (ACIP). To obtain a full understanding of these schedules, it is vital to visit the CDC’s website to read the annotations attached to each set of recommended immunizations and to do so as frequently as these recommendations are updated.2 Travel abroad may also pose the risk of exposure to infectious agents not normally encountered in the United States, and additional immunizations may therefore be required. Recommendations related to travel vaccinations are provided separately in the CDC’s Yellow Book.

The CDC reminds us that immunizing individuals contributes to community health, especially by protecting people who cannot be immunized because they are either too young to be vaccinated, cannot be vaccinated for medical reasons, or cannot make an adequate response to vaccination because of poor health or a compromised immune system.2 Widespread immunization programs can eliminate or reduce the impact of epidemics and disease outbreaks by elevating the overall health of a community.

Pharmacy Role

As members of the healthcare community, pharmacy staff members are often involved in initiatives to make immunizations, and accurate information about them, available as widely as possible. Emphasizing reliability and safety are key components of the communication provided related to vaccines. Pharmacy staff can participate in a multitude of activities related to immunization stewardship; these include managing supplies, promoting immunization, and facilitating the administration of vaccines.

Managing the supply of immunizations in the community and in healthcare institutions is a complex process in which pharmacy technicians frequently play a vital role. Because they are biologic products, vaccines and toxoids are frequently issued a short shelf-life; consequently, inventory control, stock rotation, and careful ordering practices are necessary to avoid running out of these important products at an urgent time while simultaneously preventing the waste of funds and product. Records of products received, dispensed, and administered (including lot number and expiration dates) are often maintained in the pharmacy as well.

The application of knowledge to ensure proper vaccine transport and storage is an additional responsibility of everyone in a pharmacy where these products are received, handled, and stocked. Most vaccines must be refrigerated or frozen continuously prior to use, and allowing an immunization to reach a temperature that is outside the range in its labeling (eg, thawing a frozen product, freezing one that should be kept at refrigerated temperatures, letting a product that must be kept cold reach room temperature, or maintaining a vaccine outside of its temperature range) can damage it irretrievably. Inappropriate storage may render a product unable to effectively provide protection to an individual, and such potentially deadly failures of immunization are often difficult to immediately detect. Observing and maintaining the storage conditions on the labeling of each package is always required. Most vaccines must be shipped in an insulated container, and many have an enclosed temperature monitor to verify that they have not been exposed to temperatures outside their recommended storage ranges; reviewing such conditions upon receipt will ensure that vaccinations have not been inappropriately handled in transit. Pharmacy personnel must note the beyond-use date of received products, and immediately place the products in appropriate storage conditions with those expiring first in the most accessible position. The CDC has published a “Vaccine Storage and Handling Toolkit” which provides updated specific information pertaining to the proper storage of immunizations.2 The importance of proper vaccine storage and handling is difficult to overstate, especially related to immunizations that need to be stored in unique environments with dynamic supplies available, such as some of those used as vaccines against COVID-19.

Many vaccines require reconstitution before use. It is common for them to be packaged with their own diluents, and, if so, these are the only acceptable agents for the reconstitution process. All reconstitution should be done exactly according to package directions.

Promoting recommended immunizations is an activity in which pharmacy personnel should engage. While knowledge of immunization schedules and vaccine-related informational resources are helpful in ensuring that patients are up to date with vaccination, recent history poses another challenge regarding immunizations related to the public faith in this process that has provided our society with so many remarkable health benefits. Maintaining vaccine confidence requires that pharmacy personnel work toward reaffirming personal and public trust in vaccines, the administrators of immunizations, and regulations surrounding immunizations. Doing so is of paramount importance when considering the monumental impact of immunizations on maintaining public health and, given the time at which this was written, in the use of immunizations in combating the COVID-19 pandemic. While authentic feelings of concern are often at the root of an individual losing vaccine confidence, vaccine confidence can often be maintained or restored by sharing information rooted in the correct interpretation of evidence and connecting this information to how immunizations may assist in maintaining wellness by safely preventing disease when used as recommended. For a pharmacy professional, it is vital to be aware of the answers to questions about vaccines to increase vaccine confidence, and to be skilled enough to communicate such information in a tactful way to patients who genuinely care about their health and that of their families.

Several key basics are necessary when presenting information to an individual who is skeptical regarding immunizations. It is often necessary to first recontextualize the benefits of vaccinations for these people. Current generations are extremely fortunate to be reaping the benefit of vaccines without having witnessed many of the reasons why they were created. Diseases such as smallpox, polio, influenza, measles, mumps, rubella, pertussis, tetanus, and many others plagued and killed our ancestors but are relatively rare in the modern era. It is very easy for individuals to not conceptualize vaccines as a cause for why these diseases are more absent and, because these diseases are now uncommon, downplay the danger of these infections. As COVID-19 has manifested as one of the most threatening infectious events in recent history, the impact of an unchecked pandemic has unfortunately become more apparent in modern times, especially to those individuals and families most closely affected by this disease. While changes to day-to-day routines such as mask wearing, social distancing, and limiting social contact are vital means to slow the spread of a potentially life-threatening infection, history and modern data indicate that vaccination is an extremely important tool to assist with ending a pandemic and curtailing avoidable serious health complications brought by COVID-19. It is vital to understand that immunizations have saved countless lives by conferring active immunity against many deadly pathogens, and our society will only be able to remain protected against these diseases and emerging threats if immunization is continued.

Another basic piece of communication corresponds to understanding one of the main roots of losing vaccine confidence: misinformation. Access to virtually unlimited information has emerged, but much of this information is of dubious quality. Numerous web pages, social media groups, and social media posts allow individuals to “confirm” incorrect information or misinterpretation by repeating it; this can make it very challenging to help an individual come to correct conclusions as they are often victims of receiving information from unreliable sources. Encouraging individuals to critically evaluate the sources of their information and specifically stating the value of peer-reviewed literature and conversations with healthcare professionals may inspire realizations regarding the credibility (or lack thereof) of their sources.

In addition to the knowledge and communication of the societal necessity of immunizations, as well as the importance of reliable information sources, understanding the truth regarding common ideas that threaten vaccine confidence is key. Misgivings regarding ingredients, the administration of several vaccines simultaneously, adverse events related to immunizations, and the efficacy of vaccines often permeate conversations about the appropriateness of immunizations.

Knowledge of the purpose and safety of various immunization ingredients is vital to accurately understanding and communicating information related to vaccines. Ingredients that have garnered attention, their uses, and information related to their safety are presented in the following:

• Formaldehyde is an essential ingredient utilized to chemically inactivate viruses such as the poliovirus and detoxify bacteria such as Corynebacterium diphtheriae, which causes diphtheria, to eliminate the possibility of harm from such pathogens. While toxic in large concentrations (as any medication may be), the amount of formaldehyde in vaccinations is negligible compared to that which the body produces on its own.

• Aluminum is present in various immunizations such as the diphtheria toxoid/tetanus toxoid/acellular pertussis (DTaP) vaccine, pneumonia vaccines, and the HBV vaccine. Aluminum functions as an adjuvant in immunizations, which means that it helps boost the immune system’s response to the antigen introduced by the vaccine. It has demonstrated safety over six decades of use, and aluminum is commonly encountered in food and water. While hesitant individuals may counter that “ingestion does not equal injection,” the absorption of aluminum from immunizations is nonthreatening based on its historically safe use, as well as pharmaco*kinetic models of metabolism in several age groups (including infants).

• Fetal calf/bovine serum functions as a nutrient-rich environment that helps to grow virus particles utilized for various immunizations. This serum is also a common laboratory growth medium that works to foster the replication of organisms exposed to it. While this serum is derived from fetal calves, it works as nothing more than a growth environment during the manufacturing of certain immunizations.

• MF59 is an adjuvant that works to boost the immune system’s response to a specific influenza vaccine. It utilizes squalene, which is a natural component of the cholesterol pathway in our bodies, and its safety is well established.

• AS01B is another adjuvant utilized in a specific vaccine against shingles. Its two components, MPL and QS-21, work together to boost the body’s ability to fight against the shingles virus antigen introduced by the vaccine. MPL is a fat-like substance, and QS-21 is a compound purified from tree bark.

• Antibiotics are utilized to prevent bacterial contamination of immunizations during the manufacturing process and are almost entirely filtered out during the end-stage production of vaccinations. Notably, antibiotics that may trigger allergic reactions in individuals (eg, penicillin agents and sulfa drugs) are not utilized.

• Thiomersal/Thimerosal is an ethylated mercury-containing compound utilized as a preservative in some immunizations. It was infamously and incorrectly linked to autism spectrum disorder in a since-discredited study; more recently, multiple nationally sponsored studies have rejected any association between this compound and autism spectrum disorder.3 It was removed from most immunizations to curb overall mercury exposure despite historical safe use, and individuals still concerned regarding this compound can complete the CDC vaccination recommendations with products entirely free of thiomersal.

Individuals may also express noningredient-related concerns regarding immunizations. Apprehension related to administering multiple vaccines at once is dispelled by the safe use of vaccine combinations dating back to the 1940s, and immunizations that are recommended to be utilized alongside one another are tested in such settings to ensure safety. Some individuals may cite the National Vaccine Injury Compensation Program as evidence that immunizations are malicious or meant to cause harm. It is critical, however, to understand that immunizations are capable of causing rare adverse effects, like all other medications. Such adverse effects may occur following the inappropriate administration of a vaccine, represent an allergic reaction, or be due to the utilization of a vaccine in an individual without a functional immune system. In addition, adverse effects may occur near the timing of an immunization but have no relation to the vaccine itself. A compensation program, contrary to this argument, is evidence of the importance of vaccinations; it exists, in part, to prevent the threat of lawsuits, regardless of merit or immunization causality, from discouraging the production of immunizations.

Some individuals avoid receiving elective immunizations as they do not want to “get sick” from the vaccine. It is important that pharmacy professionals understand the difference between the brief period of fatigue that may follow an immunization and the actual illness in question so that they can explain it to patients. First, it is impossible to contract an illness from a nonlive immunization, as there is nothing in such a product that may confer disease. Live vaccines are weakened, or attenuated, which prevents individuals with a functional immune system from harm; these immunizations, however, are contraindicated in immunosuppressed individuals because the weakened pathogen may be able to cause harm in such cases. Feeling sick after an immunization may represent an increased period of immune system activity (ie, the reaction associated with antigenic exposure), but this must not be confused with actual infection in individuals with a functional immune system.

The influenza vaccine also receives criticism regarding its utility. Individuals may question its purpose and usefulness related to the CDC’s recommendation of one dose each year. This recommendation is rooted in the nature of influenza as a pathogen, for this virus possesses the ability to change its unique antigenic structure over time. Because of this characteristic, the influenza vaccine administered one year may not adequately protect an individual from variations of the virus that may circulate in the future. Scientists work to combat this by developing vaccinations against the most current influenza virus each year; this is why annual vaccination is necessary to confer protection against this deadly pathogen. Various formulations of the influenza vaccine exist, which vary based on the strength of the dose; how many strains of the virus the immunization affords protection against (eg, three strains, or trivalent, vs. four strains, or quadrivalent); whether the virus is live, recombinant, or inactivated; and whether it contains an adjuvant. It is generally recommended that older adults receive a high-dose formulation, but other individuals will likely receive adequate protection with any age-approved vaccine appropriate for their health status. Additionally, individuals with an egg allergy should still receive the influenza vaccine after consulting their healthcare provider regarding this matter. Annual vaccinations will work to protect both individuals and their close contacts from transmission of this virus each year.

The COVID-19 pandemic has provided yet another reason to emphasize the importance of vaccine confidence, but the recent advances in COVID-19 immunizations have arrived with new challenges in maintaining public trust. Avoiding the potential for serious health consequences related to COVID-19 has driven the consistent production of information during the pandemic, and misinformation has also circulated in this dynamic environment. Because vaccine confidence related to COVID-19 represents an important public health priority, understanding how to communicate reliable facts to dispel misinformation related to vaccination for COVID-19 is critical.

The CDC publishes a frequently updated collection of web pages dedicated to building vaccine confidence related to COVID-19 vaccines and understanding correct information related to common misconceptions related to these immunizations.4 They recommend several resources and action steps to help affirm COVID-19 vaccine confidence by building trust, empowering healthcare personnel, and engaging communities as well as individuals.

Having successful conversations with friends and family first requires understanding key facts related to COVID-19 vaccines. A fundamentally important truth is the knowledge that COVID-19 vaccines are both safe and effective for use. While concerns may be raised related to the initial use of an Emergency Use Authorization (EUA) for these products as opposed to a more traditional U.S. Food and Drug Administration (FDA) approval, reviewing what an EUA entails provides understanding and confidence related to this part of the vaccination regulatory process. An EUA is a means through which the FDA will allow use of unapproved medical products in an emergency to diagnose, prevent, or treat serious or life-threatening diseases when there are no adequate, approved, or available alternative options. It is paramount to know that, for an EUA to be issued by the FDA for a vaccine, the FDA must decide that any definite or possible benefits of the vaccine outweigh any definite or possible risks. COVID-19 vaccine clinical trials are being held to the high safety and effectiveness standards set by the FDA, and each vaccine provided an EUA by the FDA undergoes three phases of preapproval clinical trial research similar to all other medications. This rigorous process, in addition to intimate knowledge related to how these vaccines work and the evaluation of the manufacturing of these products, factor into the FDA’s decision with respect to the appropriateness of issuing an EUA. Postauthorization monitoring is also robust and conducted for each authorized product. Understanding the gravity of an EUA helps to engender vaccine confidence in products assigned such an authorization.

Reviewing the mechanisms related to mRNA vaccination and adenovirus vector vaccination will also help to satisfy concerns related to the safety of these vaccines. As reviewed above, these vaccines provide a blueprint for the body to produce a harmless antigenic protein that confers active immunity to COVID-19. These blueprints are destroyed by cellular machinery after use, and they cannot affect host cell DNA. Therefore, there is no potential for COVID-19 vaccines to alter human DNA. This string of molecular events helps to clarify that it is unlikely that these vaccines may affect fertility; this, in combination with early real-world data, helps to establish the likelihood of safety of these vaccines for those who would like to become pregnant in the future. At the time of writing, the CDC strongly recommends COVID-19 vaccination, if otherwise appropriate, for patients planning a pregnancy, those trying to become pregnant, and in those who might become pregnant in the future. This is related to the risks of COVID-19 in pregnancy which include severe illness, death, and pregnancy complications. The CDC also strongly recommends that pregnant patients receive the COVID-19 vaccine, if otherwise appropriate, related to avoiding the above risks and when considering available data pertaining to the safety and effectiveness of mRNA vaccines. However, as this is a developing area, it is important to refer to current guidelines regarding administration of the COVID-19 vaccine in pregnant patients and to advise patients to discuss such items with their healthcare provider(s). Additionally, further research is being conducted regarding COVID-19 vaccines and pregnancy. Existing data on how these vaccines work also supports that the risk for long-term side effects is very unlikely. Individuals concerned regarding their eligibility for a COVID-19 vaccine are encouraged to discuss this decision with their healthcare professional team. It is worth emphasizing that COVID-19 vaccines cannot give individuals COVID-19 as they only introduce a harmless outer protein of the virus that causes COVID-19 as the antigenic substance.

Expectations regarding how someone might feel after COVID-19 vaccination, and why they may feel this way, are additionally important to understand. As vaccination produces an immune response, symptoms related to such a response (eg, local pain, redness, swelling, tiredness, headache, muscle pain, chills, fever, and nausea) may occur after vaccination. These side effects are likely signs that the body is mounting an immune response and, while they may impact day-to-day activities, they should go away in a few days if experienced at all. Any individual with persistent or troubling side effects should talk to their healthcare professional team, though, for guidance regarding the next best steps or actions to take to safely minimize discomfort.

Additionally, understanding that the production of full immunity related to the formation of memory cells occurs approximately two weeks after completing a vaccination series serves as a key feature of COVID-19 vaccines. These vaccines have demonstrated effectiveness in preventing infection related to COVID-19 and, after full vaccination is achieved, individuals may safely reengage in certain activities pursuant to the guidance of national healthcare-related organizations such as the CDC. While COVID-19 vaccines are safe and effective in preventing COVID-19, more information is required with respect to the effectiveness of these vaccines in preventing the spread of COVID-19 from person to person and within a community, the duration of protection afforded by these vaccines (and recommended scheduling for subsequent boosters), how effective these vaccines are against new strains of COVID-19, and how many people must be vaccinated before most people are considered protected from infection (ie, population immunity). Staying vigilant with respect to how ongoing, evidence-based studies contribute to the body of knowledge related to COVID-19 vaccination is a key feature of the scientific method and is expected of all pharmacy professionals. Organizations such as the CDC offer regular updates on their web pages to facilitate this process.

Effectively communicating correct information related to COVID-19 vaccines to build vaccine confidence also requires attention related to the conversation itself. Listening to others with an open mind and without judgment helps to establish genuine trust between parties, which will likely make it easier to find common ground and validate one another. Mutual trust and understanding may additionally be created by asking open-ended questions and asking permission to share further information and techniques for finding trustworthy information from reliable sources. It can be impactful to share reasons for getting vaccinated while helping to discover potential motivations that others may have for receiving the vaccination themselves. Finally, helping an individual make a commitment to receive their immunization, and working to make each step of signing up to receive a vaccine as easy as possible, may assist in inspiring vaccine confidence. Ultimately, sharing correct information and reliable sources related to COVID-19 vaccines must be done while respecting and appreciating the concerns of each person.

Pharmacists often administer immunizations. While state laws (pharmacy practice acts) differ in specifics pertaining to such administration, every state in the United States includes pharmacy personnel on the immunization “team.” Pharmacy technicians have usually assisted the pharmacist with administration by ensuring that stocks of immunization supplies are available, in-date, recorded appropriately, communicated successfully, and handled in a manner consistent with approved guidance. Many states require that information pertaining to immunizations be communicated by administering pharmacies to patients’ primary care physicians. Ensuring that this infrastructure is present (when required) is an additional element with which pharmacy technicians may assist. Some states permit and encourage appropriately trained pharmacy technicians to administer immunizations, and this practice is likely to become more common in the future.

Sometimes, conferring passive immunity to diseases or toxins is important, and this may be accomplished by directly administering immune globulins or antitoxins to a patient suffering from the impact of a direct immune-related insult. Passive immunity is not long lasting, but it can be accomplished much more immediately than active immunity as it does not require the patient to produce their own agents of adaptive immunity. The use of immune serum can protect individuals who have been recently exposed to a toxin, such as the venom of a poisonous reptile, from some of the dangerous or deadly effects of that toxin; these effects may occur before the immune system can develop its own defenses.

Immune globulins may also be utilized to prevent the effects of incompatible blood types in certain mothers and their fetuses during pregnancy. Some individuals possess blood with an antigen known as Rho(D) and, if a child’s blood possesses this while a mother’s does not, the mother’s immune system may develop antibodies against this component of the baby’s blood during pregnancy. This can be fatal for the child. One immune globulin has been designed to prevent the mother from developing antibodies in such cases, and it is utilized in this as well as other Rho(D)-related disease states.

Postexposure prophylaxis includes measures taken to prevent illness or infection after acute exposure of a nonimmune individual to a pathogen that can cause serious or fatal disease. This may include administration of specific immune sera/immune globulins. Examples include the hepatitis B immune globulin administered to infants born of HBV-infected mothers, the same immune globulin administered to healthcare workers with needle stick exposures, and the rabies immune globulin administered to a patient who has been bitten by a potentially rabid animal. Normal vaccines to produce active immunity against these antigens are available, but in cases where immediate protection is needed to prevent a suspected insult from causing serious damage, passive immunity may provide a timely advantage. Some patients are unable to mount an immune response to a pathogen even after vaccine administration. These include those born with deficiencies of their immune systems, patients suffering from serious illness, individuals with certain infections such as HIV, and patients being treated with medications that suppress their immune systems (ie, immunosuppressives). The state where one’s immune system is unable to produce a functional defense is known as immunocompromise. Immunocompromised patients are occasionally treated with pooled human immune globulins, which include antibodies to many commonly encountered antigens and vaccine-preventable diseases. Preparations that confer passive immunity against viral infections, toxins, or envenomation, as well as immune-related medication antidotes, are listed in Medication Table 30-3.

Immunosuppressives

While the immune system is important in enabling the body to prevent damage by infectious agents and toxins, there are times when its actions are harmful or unwanted. Sometimes the immune system mistakes the body’s own cells and tissues as foreign and attacks them; conditions defined by such actions are known as autoimmune diseases. Autoimmune conditions such as rheumatoid arthritis and systemic lupus erythematosus have been discussed earlier (Chapter 13) and are often treated with medications that intentionally suppress the immune system (ie, immunosuppressives).

It is sometimes necessary for patients whose tissues or organs have been damaged beyond repair by disease or injury to receive similar tissues or organs from others to replace their own. These procedures are called transplants or grafts, and they may involve whole organs (eg, lung, heart, liver, kidney) or tissues (eg, skin, bone marrow). In these cases, the immune system may, albeit correctly, recognize the transplant as foreign and attack it. This phenomenon is known as rejection and can cause failure of the transplant and possibly fatal harm to the transplant recipient. Immunosuppressives are often utilized in this setting to help prevent the incidence of rejection.

Corticosteroids, discussed in detail in Chapter 9, are effective in suppressing the immune system and may be used to avoid the rejection of transplants, sometimes even while the transplant surgery is still in process. While these medications (eg, IV methylprednisolone and oral prednisolone) have immunosuppressive properties, they are more often utilized in other medical conditions (eg, to decrease inflammation), which makes the risk of immunosuppression an unwanted adverse effect in such instances. Doses of glucocorticoids to prevent rejection are often much higher than doses used for most other medical conditions.

Medications known as antimetabolites (covered in Chapter 31) encompass a broad class that uniformly trick the body into incorporating dysfunctional molecules into chemical reactions required to sustain cell life; this interrupts these critical processes and works to destroy the functionality of the affected cell. Consequently, most antimetabolite medications have uses as anticancer agents. Use of these agents may, however, risk suppressing the immune system as an adverse effect. One antimetabolite, azathioprine, targets specific cells of the immune system, which allows it to be utilized for indications that are not related to cancer. Specifically, it is available as an oral or injectable agent to prevent the rejection of kidney transplants, and it is also used for other immune-related conditions. Because it reduces WBCs, patients taking azathioprine are more susceptible to infection. Azathioprine also bears a black box warning because it increases the risk of malignancy. It is administered with food to decrease the incidence of gastrointestinal side effects.

Much more specific immunosuppressants have been developed during the past several decades. Mycophenolate is one such agent that directly suppresses the immune system by preventing the development of T and B lymphocytes. The hydrochloride (injection) and mofetil, mycophenolic acid, and sodium (oral) preparations may be utilized as a component of an antirejection regimen for cardiac, liver, lung, or kidney transplantation. Although it is a more specific agent, mycophenolate possesses a host of adverse effects due to its interference with widespread cellular processes. These include predisposing a patient to infections, certain blood disorders (eg, anemia), pain, and blood pressure changes. It also possesses a black box warning related to malignancies, serious infections, and fetal toxicity.

Calcineurin inhibitors are another class of immunosuppressives that decrease immune response by blocking T-cell activity, but they do so by a different mechanism than the antimetabolites. Several of their major side effects are nephrotoxicity (kidney damage) and neurotoxicity (tremors, headache, and even seizures). Infections are always a risk when the immune system is suppressed, and many of these agents consequently have black box warnings related to serious infection.

Cyclosporine (also known as cyclosporin A) is a calcineurin inhibitor available as an intravenous (IV) solution as well as capsules and a solution for oral administration. Oral formulations must be taken on a regular schedule, at the same times every day, and associated with the same meals. Interestingly, cyclosporine is produced under several brand names and is available as either a nonmodified product named SandIMMUNE or a modified product meant to have improved absorption; the modified products are marketed as Gengraf or Neoral. There is also an experimental inhaled product to prevent rejection of lung and bone marrow transplants. Cyclosporine uniquely has a black box warning related to serious elevations in blood pressure and kidney toxicity.

Cyclosporine is metabolized by the liver and has many drug interactions that can either increase blood levels (and risk of toxicity) or decrease them (chancing organ rejection). Some drugs can also have increased effects when taken with cyclosporine. A full medication profile (including herbal supplements) is critical to obtain for every patient taking this medication (and all patients).

Tacrolimus is another calcineurin inhibitor dosed as an IV solution or as several oral forms. It may be dosed once daily or every 12 hours depending on whether the immediate-release or extended-release oral formulation is utilized. These products cannot be interchanged. Like cyclosporine, it is metabolized in the liver and has many drug interactions, so a complete patient profile is required. In addition to immunosuppression, tacrolimus has an additional black box warning related to increasing the risk of certain malignancies.

Certain agents, sirolimus and everolimus, change the way T-cells respond to antigenic stimulation by inhibiting a cellular compound known as the mechanistic target of rapamycin (mTOR). Both are administered orally and are used in conjunction with other agents to prevent the rejection of various transplants, depending on the agent. These drugs, like the calcineurin inhibitors above, are metabolized by liver enzymes and have many drug interactions.

A novel type of immunosuppressant is termed a selective T-cell costimulation blocker because it prevents certain cells of the immune system from interacting with T-cells. Two medications of this class are belatacept and abatacept. The former is utilized to prevent rejection in kidney and lung transplants, while the latter suppresses the immune system from causing joint inflammation in conditions such as psoriatic and rheumatoid arthritis.

The most common adverse reactions to the T-cell costimulation blockers are infection, anemia, gastrointestinal effects, cough, and headache. More concerning reactions are the serious and life-threatening malignancies that involve the lymphatic and central nervous system. There are few drug interactions, except with other agents that affect the immune system.

Several IV antibody preparations have been developed as immunosuppressants. The antithymocyte globulins are polyclonal antibodies as they bind to several lymphocyte proteins; monoclonal antibodies, however, bind to one target. These antithymocyte globulins are derived from either horse or rabbit tissue and work by binding to the receptors on lymphocytes to prevent them from attacking transplanted tissue. Their main adverse effects are suppression of blood cell formation, anaphylaxis, rash, breathing difficulties, and cardiovascular issues (heart and blood pressure).

A third antibody, muromonab-CD3, is a monoclonal agent specific to the CD3 receptor of the mature human T-cell. It is no longer available due to a voluntary withdrawal from the market.

Several monoclonal antibodies may be used to prevent rejection. One product is available that works against certain receptors on activated T-cells to prevent them from attacking transplanted tissue. This agent, basiliximab, binds to the interleukin-2 (IL-2) complex to elicit its immunosuppressive effect. It is indicated for use in conjunction with other immunosuppressives for preventing various types of organ rejection and, like other antibodies, it is administered intravenously. Side effects include hypertension, headache, tremor, gastrointestinal effects, and infection. It has not been associated with significant drug interactions other than compounded immunosuppression with similar medications.

Rituximab, a monoclonal antibody targeted against a specific complex found on B-lymphocytes known as CD-20, is utilized primarily as an anticancer agent as well as an agent against immune-related joint disorders. It may also assist with rejection in heart transplantation by suppressing the antibody-mediated response produced by B-lymphocytes. Black box warnings for this medication correspond to infusion reactions, mucous membrane reactions, and rare infections. Premedication often occurs with at least acetaminophen and an antihistamine to minimize the risk and severity of infusion reactions. Blood cell suppression, fatigue, lung disease, and cardiac dysfunction represent more common adverse effects. Interactions are similar to other antibodies discussed.

Alemtuzumab is another monoclonal antibody that may be used to combat rejection in heart, lung, or renal transplantation by facilitating the destruction of several immune cells by binding to a specific molecule found on several such cells. Accordingly, it possesses black box warnings related to bone marrow suppression and infection in addition to the possibility of infusion reactions; the latter effect requires premedication to be given prior to infusions similarly to rituximab. This medication risks enhanced immunosuppression when combined with other immunosuppressives, and its use will likely result in headaches and a skin rash.

As discussed in the chapters on the musculoskeletal system (Chapter 13), lower GI (Chapter 22), and dermatologic disorders (Chapter 33), certain immune-related medications target other points to decrease autoimmune activity for nontransplant purposes. Medications such as tofacitinib inhibit an intracellular chain reaction mediated by the Janus kinase (JAK) proteins. Stopping this pathway works to shut down certain immune cells with the goal of treating psoriatic arthritis, rheumatoid arthritis, and ulcerative colitis. Additionally, anakinra is a medication that inhibits the IL-1 receptor to decrease immune-related inflammation in conditions such as rheumatoid arthritis. A last group of monoclonal antibodies, including adalimumab, work to downregulate a mediator of inflammation known as tumor necrosis factor-alpha (TNF-alpha). Such action has proven beneficial in a multitude of musculoskeletal, gastrointestinal, and dermatological conditions. While not utilized for rejection, these medications still predispose patients to infections by generating an immunosuppressive state.

The noncorticosteroid immunosuppressive agents that are used as components of regimens to prevent and treat organ rejection are summarized in Medication Table 30-4. Of note, individual agents are often utilized in combination with several other immunosuppressive medications to compose a complete antirejection regimen.

Biosimilars

In recent years, biotechnology and regulation have been used to facilitate the safe production of cost-effective alternatives to certain biologic medications (ie, isolated from natural sources as opposed to chemically synthesized). These alternatives are known as biosimilars. Unlike generically equivalent medications, biosimilar products are biologic agents that possess slight differences from the compound that they mimic; the compound that a biosimilar copies is more formally referred to as a reference product. While these variations initially sound alarming, a biosimilar must be designated by the FDA as “highly similar” to the reference product without possessing “clinically meaningful differences.” A “highly similar” product is one that has undergone extensive testing to evaluate the structure, function, and purity of the proposed biosimilar against the reference product. Approved biosimilars must then possess “no clinically meaningful differences” that may stem from any imperfect elements of the comparison, and various clinical tests are often utilized to verify the absence of such differences. In addition, approved biosimilars may be given status as an interchangeable product; approved biosimilars may be substituted with the reference product only with physician approval, but those designated as interchangeable products by the FDA meet additional standards of similarity that allow them to be substituted for the reference product without prescriber approval (pending state regulations).

Currently approved biosimilars represent several classes of medications, including the aforementioned TNF-alpha inhibitors and anti-CD-20 agents, as well as medications that help the body produce blood cells (eg, colony stimulating factors). Anticancer agents that work against the vascular endothelial growth factor (VEGF) and human epidermal growth receptor 2 (HER2) are also classes of medications with biosimilars.

Biosimilars represent an exciting new wave of medications that may allow costs to be driven down for normally expensive biological products, and the FDA’s Purple Book lists approved biosimilars and interchangeable products. Approved biosimilar products as of March 2022 are provided in Medication Table 30-5.

SUMMARY

The immune system is the body’s main defense against disease caused by invading pathogens and the toxins they may produce. While innate immunity is important, acquired immunity enables the body to fight off specific infectious diseases. Active immunity, associated with exposure to pathogenic agents, can be induced by vaccination, which confers protection against specific diseases without causing infection and related consequences. Vaccinations against many diseases have reduced their incidence, eliminated their presence, and improved the quality of life for society in general. Understanding their necessity and safety while communicating such information tactfully is becoming more important each day, especially in the context of the COVID-19 pandemic.

Passive immunity can be conferred by directly transferring antibodies from another source. It is relatively immediate, short-lived, and useful in protecting patients who have been infected or exposed to an acutely dangerous pathogen or toxin to which they have no prior immunity.

In some cases, it is advantageous to suppress the immune system. This is especially true in organ transplantation, when the body’s natural response is to attack (reject) the foreign tissue. Using immunosuppressant agents prevents this reaction and allows a transplant to have maximal levels of success. Immunosuppression, while useful in this way, confers a risk of serious adverse effects and alters patients’ candidacy for certain immunizations.

Over the next several years, unique and more cost-effective alternatives to many medications, including biologics, will likely emerge. Staying informed on the progression of biosimilar products will ensure that all patients receive the most appropriate medications at all times.

ACTIVITIES FOR REVIEW

1. Describe the differences between innate and acquired immunity versus active and passive immunity.

2. Define the different types of vaccines, and list pertinent differences between these types.

3. Explain how pharmacy personnel can contribute to public health by supporting immunization. List ways for pharmacy personnel to enhance vaccine confidence.

4. Utilize the CDC vaccination schedule to understand vaccinations required for children, adolescents, and adults.

5. Explain why immunosuppression is necessary for patients who have undergone organ transplantation, and name three categories of immunosuppressive medications.

6. Describe how biosimilars differ from generic medications in terms of composition and regulation, and explain the differences between products designated as “biosimilar” or “interchangeable.”

MEDICATION TABLES