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HA PTER TZ unobiologicals NM BEALE, JR E immune system constitutes the body"s defense against Eollous agents. li protecis the host by identifying and elim- ornewtralizing agents that are recognized as nonself. Re entire range of immunological responses affecis essen- every organ, tissue, and cell of the body. Immune re- &s include. in part, antibody (Ab) production, allergy., pulion, phagocytosis, cytotoxicity, Lransplant and [A no rejecton, and the many signals that regulate these ses! At its most basic, the human immune system be described in terms of the cells that compose it. Every of the immune system, whether innate and nonspe- adaptive and specific, is controlled by a set of special- Is. Thus, this discussion of some of the fundamentals ologv begins with the cells of the immune system E 5 OF THE IMMUNE SYSTEM ne cells derive from pluripotent stem cells in the RE marmow, These are cells that can differentiate into any Ee bell type, given the might kind of stimulus (Scheme 7- EA variety of modes of differentinton beyond the stem dd pve mise to unique cellular types, cach with a specific 2a, 4 in the immune system. The first stage of diflerentia- m gives nse to two intermediate mypes of stem cells and us, es a branch point” These cells are the myeloid cells log O lineage) and the Iymphoid cells (Iymphoid lime- à! ing the lincage further leads to additional branch- E The myeloid cells differentiate into erythrocytes und s and also monocvtes and granulocytes. The Hold cell differentiates into B cells and T cells, the cells ta. y me né the center of adaptive immunity. The switching m for cach pathway and cell type is governed by a uf colony=stimulating factors, stem cell factors, and ans, These control proliferation, differentiation, and pm of the cells Histocompatibility Antigens—Self Monself nt of most immune responses depends on nition of what is self and what is not self. This on must be clear and must be done in a very il way. This recognition is achieved by the expression ulized surface markers on human cells. The major p of markers involved in this recognition consists of ins, These are referred to as the major histocom- ly complex” (MHC) or major histocomparibility anti- E Proteins expressed on the cell surfaces are class 1 Cs und class 1 MHCSs. Both classes are highly polymor- E amd so are highly specific to cach individual. Class | MHCs can be found on virtually all nucleated cells in the human body, while class IE MHC molecules are associated only with B Iymphocytes and macrophages. Class | MHCs are markers that are recognized by natural killer cells and evtotoxic T Iymphocvtes. When a class | MHC is coex- pressed with viral antigens on virus-infected cells, cyrotoxio target cells are signaled. Class 1] MHC molecules are mark- ers indicating that 4 cooperative immune state exists between immunocompetent cells, such as between an antigen-pre- senting cell and a T-helper cell during the induction of Ab formation, Granulocytes* If one views a granulocyte under à microscope, one can observe dense intracytoplasmic granules. The granules con- tain inflammatory mediators and digestive enzymes that de- stroy invading pathogens, control the rate and pathway of migration of chemotactic cells, and cause dilation of blood vessels at the infected site. The increased blood flow ensures that an ample supply of granulocytes and inflammatory me- diators reaches the site of infection, There is à family of granulocytic cells, cach member with its own specialized function. Under microscopic examination, some gramulo- cytes are seen to be multinuclear and some mononuclear The configuration of the nuclear region and the staining be- havior provide ways of classifying granulocytes. The group is discussed below Neutrophils” Newtrophils are the primary innate defense against patho- genic bacteria. They make up most (50 to 75%) of the leuko- eyte fraction in the blood, Microscopically, neutrophils have multilobed nuclei, They respond to chemical motility factors such as complement mediators released from infected or in- flamed tissues and migrate to à site of infection by the pro- cess of chemotaxis. There, they recognize, adhere to, and phagocytose invading microbes. Phagocytes The phagocytic process is initiated by contact and adhesion of an invading cell with a phagocyte cell membrane. Adhe- sion tniggers à process whereby the phagocytic cell extrudes pseudopodia that surround the adhering microbe, As this process progresses, the microbe is actually surrounded by the phagocyte cell membrane, Then, invagination of the membrane fully engulfs the particle, and the membrane 15 rescaled, with the particle encased inside an intracelular vacuolar body called a phagosome. Lysosomes in the cyto- plasm then fuse with the phagosome to form phagotyso- 197 198 Wilson and Gisvold's Texibook of Orpanio Medicinal and Pharmaceutical Chemistry Erythrocytes and | | New Stem Cells Asymmetric Mitosis — — Myeloid Branch |-———————+ = f Pluripotent Stem Cells ) 7 á a [— em Lymphoid | Branch er À 1 2 À Platelets | nocyte | Macrophage Ee À -—— Neutrophil 8 Lymphocytes | Basophil | Eosinophil nn T Lymphocytes | [Mest Cells — — * Natural Killer Cell Scheme 7-1 = Lineages of blood cells. Al| blood cells derive from a pluripotent stem cell, A variety of cytokines direct the cells into their specific populations somes. The antimicrobial compounds in the phagosomes and lysosomes kill the engulfed pathogen and enzymatically cleave its remains into smaller pieces Eosinophils” Eosinophils are granulocytes that can function as phago- eytes, but much less efficiently than neutrophils can. They are present as 2 to 4% of blood leukocytes. Their name derives from the intense staining reaction of their intracellu- lar granules with the dye cosin, Eosinophil granules contain inflammatory mediators such as histamine and leukotrienes. so dt makes sense that these cells ure associated with the ullergic response. Clues to the funetions of cosinophils come from their behavior in certain discase states. Eosinophil counts are elevated above normal in the tissues in many different diseases, but they are recognized primarily for their diagnostic role in parasitic infections and in allergies. Eosin- ophils have a unique mode of action that lends to their ex- treme importance. Unlike neutrophils, cosinophils need not phagocvtose à parasite to kill it. Indeed, some parasites are too large to allow phagocytosis. Bosinophils can physically surround a large parasite, forming a cell coat around the invader. Eosinophil granules release oxidative substances capable of destroying even large. multicellular parasites. Hence, even when phagocytosis fails, a mechanism exists to destroy large parasites. Mast Cells and Basophils Mast cells and basophils also release the inflammatory me- diators commonly associated with allergyv. Mast cells are especially prevalent in the skin, lungs, and nasal mucosa; their granules contain histamine. Basophils, present at only 0.2% of the leukocyte fraction in the blood, also contain histamine granules, but the basophiles found circulating in the blood and not isolated in connective tissue. Both mast cells and basophils have high-affinity immunoglobulim E (IgE) receptors, Complexes of antigen molecules with IgE receptors om the cell surface lead to cross-linking of IgE and distortion of the cell membrane, The distortion causes the mast cell to degranulate, releasing mediators of the allergio response. Because of its association with hypersensitivity; IgE has been called ““reagin” in the allergy literature, Diags nostically, IgE levels are elevated in allergy, systemic lupus erythemutosus, and rheumatoid arthritis. Cromolyn sodium is a drug that prevents mast cell degranulation and thus blocks the allergie response, Cromolyn is used in asthma, Macrophages and Monocytes* * Macrophages and monocytes are mononuclear cells that arm capable of phagocytosis. In addition to lheir phagocytic ca pabilities, they biosynthesize and release soluble factors tcomplement, monokines) that goverm the acquired immune response, The half-life of monocytes in the bloodstream à about 10 hours, during which time they migrate into tissues and differentiate into macrophages. A macrophage is a ter minally differentiated monocyte. Macrophages possess & true anatomical distribution because they develop in the tis sues to have specialized functions. Special macrophages um found in tissues such as the liver, lungs, spleen, gastrointeste nal (GI) tract, Iymph nodes, and brain. These specific macros phages are called either histiocytes (generic term) or by cer tain specialized names (Kupfter cells in liver, Langerhant cells in skin, alveolar macrophages im lung) (Table 7-1). The entire macrophage network is called the reticuloendorhelinl svstem, Other macrophages exist free in the tissues, where they carry out more nonspecific functions, Macrophages kill more slowly than neutrophils but have a much broader spee- trum. H has been estimated that more than 100 soluble inc Aammatory substances are produced by macrophages. These substances account for macrophages” prolific abilities to dis rect, modulate, stimulate, and retard the immune response Mucrophages possess à very specialized function; they 200 Wilson and Gisvold's Texthook of Organic Medicinal and Pharmaceutical Chemistry gen via the B surface Ab and T-cell receptors. lt is this step that transfers specificity and memory information from the determinant into the immune system through the modularion of B-cell differentiation. Under the regulatory influence of the helper T cells, B cells are stimulated to differemtiate into plasma cells that produce Ab. The helper 'T cells accelerate and retard the process as necessary. Thus, unlike the granulo- cytes, which have only destructive functions, monocytes and macrophages regulate and program the immune response. The Lymphoid Cell Line: B and T Cells”? The Iymphoid cell line differentiates into two types of Iym- phocytes, the B lymphocytes and the T lymphocytes. These cells constitute only about 20 to 45% of blood leukocytes. They are small cells, only slightly larger than an erythrocyte, but B and T cells can be identified microscopicallv by large nuclei that occupy most of the cytoplasmic volume, The nuclei are large to contain enough DNA to enable the T and B cells to biosynthesize massive amounts of protein needed to carry out their immune functions. T Iymphocytes are in- volved in cell-mediated immunity; B lymphocytes differen- late into Ab-producing plasma cells, B Iymphocytes express antibodies on their surfaces that bind antigens. T Iympho- cytes express specialized T-cell receptors on their surfaces that bind major histocompatibility complex | (MHC-=1) and 2 (MHC-2) complexed with antigenic peptide fragments. IMMUNITY Immunity in humans can be conceptualized in a number of different ways, TF justthe type and specificity of the immune response are considered, the ideas of innate and acquired immunity are used. If only the components that are involved in the immune response are considered, the processes can be divided into fumoral and cellular immunity. If the loca- tion of the immune response is considered, we find that the immune system consists of serosal (in the serum) immunity and mucosal (on mucosal epithelium surfaces) immunity. Innate Immunity Innate immunity is the most basic form of immunity and includes immune systems that are present in à human from birth. A clear distinction must be made between innate im- munity and acquired (adaptive) immunity, which develops after birth, and then only after an antigenic challenge (Table 72), Innate immunity is the first line ol defense against TABLE 7-2 Characteristics of Innate Versus Acquired Immunity Innate Immunity Acquired Immunity Present from binh Develops later Rapid Sluw Nonspecific Specific No memory Memory invasion by microbes and can be characterized as fast in response, nonspecific, and lacking in memory of the chal- lenge. Acquired immunity develops through a complex system of reactions that are triggered by invasion with am infectious agent. It is slow in response to an infection, is highly specific, and has memory of previous infections, The memory. or anamnestic response, is responsible for the extremely rapid development of the immune response with subsequent challenges and is a hallmark of acquired impmmunity There are three separate components of innate immunity that work in concert to provide the whole response. There are physical barriers, cellular barriers, and soluble factors The physical barmiers include the largest, mostexposed orgm of the body (the skin), the mucosa, and its associated mucus The keratinized layer of protein and lipid in the stratum cor neum of the skin protects physically against a vanety of environmental, biological, and chemical assaults. The por tection afforded by mucosal surfaces, such as are found iu the throgt, mouth, nose, and GI tract, is due to a surtiu epithelium. The epithelium consists of single or multiple layers of epithelial cells with tight gap junctions betweem) them. This type of structure provides an impermeable phys cal barrier to microorganisms. Most of the time, epithelimm) is further protected by the secretion of mucus, such as fr) gobler cells in the GI mucosa. Mucus is à viscous layer consisting of glycopeptide and an acidic glycoprotein caliah “cha mucin. Mucus can prevent penetration of microbial cells ini) the epithelium, significantly decreasing the possibility of fection by the mucosal route. Other components of the phys: cal barmers in innate immunity are the tears (containing lyas zyme), the acidic pH of the stomach. the low pH and flom of the urine, and the cilia in the lungs that constanty bes upward to remove inspired particulates and microbes. Two components of the cellular innate immune response have already been discussed, granulocytes in the blood un) tissue macrophages. When an infection occurs in the tisges chemotactic factors liberated at the site migrate down a our centration gradient to the surrounding area. These agem make the capillary beds porous. Neutrophils follow the co centration gradient across the endothelium to the site of fection. There are three types of chemotactic factors: Md formyImethionyl (f-Met) peptides released from the inal ing bacteria, (b) Ieukotrienes secreted by phagocyies, a tc) peptide fragments released from activated complemel proteins such as Cs, and Cs. Neutroplhils and macrop engulf and destroy microorganisms by phagocytosis, Nu phagocytie cells are also involved in the innate imunda sponse, providing soluble chemical factors that enhance é innate response. Soluble factors of innate immunity include (a) bactencill factors, (b) complement, and (c) interferon. A bao | factor (Table 7-3) is an agent that Kills bacteria. Pe the most fundamental bactericidal factor is the acid ini stomach. Secreted by goblet cells in the mucosal epilhel lining, stomach acid is responsible for disposimp of of the microbes that are consumed orally. Phagocyes hepatocytes produce the other bactencidal factors, Mo these are directed toward the phagosome, where lhe prol ested, phagocytically encapsulated bacterial cell is encho The antimicrobial factors kill the immobilized imicrobes There are two types of antimicrobial factors, (hose 1 — SPRSSSESERSEs a TABLE 7-3 Bactericidal Factors “ast im chal- mplex ih am on, 18 :HONS. de for ponse quired Formation Factor Site of Action Induçe Phagosomes Oxygen dons und rudicals Acil hydrulases Catonic proteins Delensins Preformed Lynne Phugosomes Preformed Phagosomes or extraçelhatar Preformed Lactofemn : Pa UA nunity pa age There aCiors, torgan TUCAS. €m cor- ery of é pró- und in urface ultiple -iwecn physi- belum s from 5 layer called lis into y ofin= are preformed inside the phagocyte and one that is induced In response to the phagocytic process. The most important of he antimicrobial mechanisms is the respiratory burst, which generates oxvgen radicais —superoxide, hydroxyl radicals, and bydrogen peroxide. The respiratory burst is the only induced mechanism. All of the active oxvgen species are highly destructive to bacterial as well as host cells, so they are not produced until they are needed. The defensins are arginine- or cysteine-rich bactericidal peptides that exhibit an extremely broad spectrum of antimicrobial activity. The defensins will kill bacteria (Gram positive and Gram nega- dive), fungi, and even some viruses. The mechanism of action afibe defensins is unknown, but since the peptides are highly gharged in an opposite sense to bacterial cell membranes. am clecirostatic, membrane-disruptive interaction might be isolved. Bucteria have an absolute requirement for iron, : physi- and to compete with the host for this element, they secrete 1g Iysos mgh-affinity siderophore factors that scavenge iron from the ud Eloy hosts stores. Lactoferrin 15 a substance produced by the ty beat host that binds iron more tightly than the bacterial chelator, E preventing the invading organism's access to a critical nu- *sponse inent. Lysozyme 1s an important component of the antimi- od and grobial system. This enzyme hydrolyzes [1-4]-glycosidic tiISSUES, 1a con- agents he com- e of ins orsy (uu) honds, as in the pepidoglycan of bacterial cell walls. Lyso- me is present in almost all body fluids, including tears amd saliva. Hepatocytes produce am array of acute phase proteins Tube 7-4) that are released into the serum during inflamma- Non or infection, These proteins do not act directly on bacte- : invado na, but they augment the bactericidal activity of other anti- tes, and qmicrobial factors. plement ophages COMPLEMENTO s. Non- iune rê- ance the tericidal tericidal Perhaps din the pithelial of most Complement is à system of at least 20 separate proteins and pofactors that continuously circulate in the bloodstream. TABLE 7-4 Acute Phase Factors Acute Phase Factor Function/Activity Chemotaxis and enhancement enscise protein cytes of phagocyiosis Most ul (eAnitrypsin Inhibition of profenses * predig- “Cemplement factors Control of the complement nelosed,. (d cascade robes. “Birinogen Blow coagulation rose that. Chapter 7 & Immiunobiologicals 201 Complement acts to kill bacterial cells that are missed by the neutrophils and the macrophages. There are actually two separate complement pathways, One, the classical pathway, operates in the adaptive or acquired immune response. The classical pathway has an absolute requirement for an Ab-an tigen complex as a trigger. The other, the alternative path way. requires no Ab or antigen to initiate and is operative in innate immunity. Both pathways operate in a tighilv regu lated cascade fashion. The proteins normally circulate às inactive proenzymes. When the pathways are activated, the product of cach step activates the subsequent step Cc Á - B-—— D E - | , E DE ne: | No star: inactive proenzyme a Star: active enzyme THE ALTERNATIVE PATHWAY In the alternative pathway, C3 is the initiating peptide (Fig.7- 2. In the serum, C3 is somewbhar unstable (il is sensitive to proteases) and spontancous|y decomposes into à large, active Câb fragment and a smaller, catalytically inactive C3a frap- ment, C3h now becomes bound to a surface, and it has two fates. We can define two types ol surfaces. One, the nonacti- vating surface, is a surface that contains sialic acid or other acidic polysaccharides. The other, an activating surface, con tains none of the acidic polysaccharides or sialic acid. This type conforms to a bacterial cell surface. Under normal cir- cumstances, C3b will bind to a nonaciivating surface, On binding, the C3b fragment becomes associated with factor H, a S-globulin that associates with an a chain on C3b Sialic acid increases the affimty for factor H 100-fold. Factor H alters the shape of C3b in such à way that it becomes susceptible to attack by factor |, a serine esterase that cleaves the e chain of C3b, producing inactive 13h. Attack by an- other protease produces a fragment designated C3c. In this pathway, factor H accelerates the decay of C3b. When fac tors H and | work together they destroy C3b as fast as it is produced and shut down the pathway [E C3b binds to an activating surface, the ability to bind to factor H is reduced, and C3b binds to à protein called factor B, forming €3bB. Bound factor B is cleaved by facto D into a fragment called Bb. The complex C3bBb has high C3-convertase activity and stimulates the pathway furiher Factor P (properdin) binds to the complex. extending the half-lite of C3bBbP. This fragment binds to the terminal complement components (€5 to 09), creating a membrane attack complex and thus Iysing the cell INTERFERONS An important antiviral system is provided by the interferons (Table 7-5 and Fig. 7-3). The interferons are peptdes that, when viral infection occurs, carry out three distinct func tons. First, they send a signal to q natural killer cell tha essentially leads to the self-destruction of the infected cell Second, they induce an antiviral state in neighboring cells, Ts of e, he us he Mi- pe- ble tic, em t5 à LIZE this som mty anti- enti- nSE- lins F of par- mu- ETE- city n be -Me- ating 2ren- iated nune erum unity + and intra- "as B gens [E] sum- press rê Cã- 3-cell kDa kDa kDa Chapter 7 = Immunobiologicals 203 Virus Neighboring Cell Virus-Resistant A o Interferon e TS f +» Ny Activity “ interferon ! & SEE o o E) ira Cell do a No Killing ado rir EEE Infected Cell Natural Killer Cells Figure 7-3 = The function of interferon. When a virus infects a host cell, the ce Interferon activates natural killer cells, causing killing of the infected host cells and elir Interferon Receptor L % resses inter nation ot the reservolr of infection. Atthe same time, interferon induçces an antiwral state in neighboring cells, effectively breaking the cycle of infection population does not differentiate into Ab-producing cells but forms a pool of cells that retain the immunological memory. Toells express a specific antigen receptor, the T-cell recep- for, similar in structure to the surface immunoglobulin recep- for of B cells. This receptor is activated by a piece of pro- tessed antigen (presented with MHC-II). Activated T cells please soluble factors such as interleukins, cytokines, inter- ferons, lymphokines, and colony-stimulating factors, all of wlnch regulate the immune response. Interactions with some df these help to regulate the B-cell activity, directing the lnate immune response THE CLASSICAL COMPLEMENT PATHWAY The classical complement pathway differs from the alterna- live pathway in that it requires a trigger in the form of an amtigen=Ab complex. Only two antibodies can fix comple- ment, 12G and IgM. The classical pathway is shown in Fig- ue 7-4, The small fragments that are cleaved from the proen- pumes have activities such as chemotacte stimulation and maphvlaxis. The bar over the names of some components ob he palhway denotes am active complex. Note that the tussical pathway does not operate with Cl to C9 in se- quence. Rather, the sequence is CI, C4, C2, €3, €5, C6. E7. CS, and €9, IMMUNOGLOBULIN STRUCTURE AND FUNCTION Au Abor lg is composed of peptide chains with carbohydrate pendant groups. A schematic of the Ab IgG is shown in Figure 7-5. The peptide chains form the quaternary structure of he immunoglobulin, while the carbohydrate moieties serve as antigen-recognition groups and probably as confor tion-stabilizing units. The general structure of the Tg looks semething like a Y, with the antigen-binding regions at the hiurcated end. In this area are peptide sequences that are “programmable”” by the immune system to allow the Ig to fecognize a lurge number of antigens Treatment with either of two enzymes, papain or pepsin, digests an Ab into fragments that are useful in understanding its molecular structure. Papain clips the Ab into two frag- menis that contain the antigen-binding regions. These frag - ments have been termed the Fab, or antigen-binding. frag ment, The remaining part of the Ab after papain digestion contains two peptide chains linked by a disulfide bond Ag-Ab C1 ' + C1 C3 Converiase [ E dá «4 Cá, C2 CAbCZb A Opsonization ” c3 C4bC2bCIb+CIb+ Ca ” * Anaplylaxis ãe Chemotaxis “ Cs C5b+C5a , Membrane Attack , Complex * C5bC6CTCACO Figure 7-4 » Classical complement pathway Disulfide Bonds Wilson amet Gisvold's Fexthook of Organic Medicinal and Pharmaceutical Chemistry Vi Antigen-Binding Regions (Fab) Fc Region | À Constant Regions Figure 7-5 e Structure of immunoglobulin G (l96), showing antigen-binding regions and key elements ot the molecule Treatment of the same Ab with pepsin yields the two Fab units joined by the disulfide bond, plus two of the distal peptide chains. These distal units have been crystallized and, hence, are termed the Fe fragment (for “crystallizable”) The disulfide bond, therefore, provides u demarcation be- tween the two molecular regions. The nomenciature of an Ab includes a high-molecular-weight, or heavy. chain on the inside and a low-molecular-weight, or light, chain on the outside. IMPORTANT FEATURES OF ANTIBODY MOLECULAR STRUCTURE? * As stuted above, the tp end of the Fab region binds antigen. There are two of these regions, so we say that the Ab is bivalent and can bind two antigen molecules. The overall amino acid sequence of the Ab dictates its conformation. The peptide sequence for most antibodies is similar, except for the hypervariable regions. The amino acid sequence at the end of the heavy chain (Fe) determines the class of the lg (i.e. 126, IgM, etc.), All antibodies resemble cach other in basic shape, but cach has a unique amino acid sequence that is complementary to the antigen in a “lock and key” interaction (antigen=Ab specificity). Some, such as IgM, are pentamers of IgG (Fig 7-6). In reality, the lock-and-key model is too simplistic, and an induced fit model is preferred. ANTIBODY PRODUCTION AND PROGRAMMING OF THE IMMUNE SYSTEM The main element of the programming portion of the im- munec system is the macrophage. À common property of muacrophages is phagocytosis, the capacity to engulf a parti- ele or cell through invagination and sealing off of the cel] membrane. The macrophages involved in the immune re- sponse set in motion a unique amplification process, so that a large response is obtained relative to the amount of antigen processed, The macrophages engulf antigenic particles and Variable Pu Hinga Region incorporate them into their cytoplasm, where the antigens am fragmented. The fragments are then combined with MHC- IH, displayed on the cell membrane of the macrophage, um presented to the immune system. The presented amtigens imeract with B cells, causing differemiation to plasma cells and Ab secretion, T-helper cells also interact with the pres sented antigen and are stimulated to cause the B cells to proliferate and mature. Plasma cells are monoclonal (genetr cally identical) and produce monoclonal Ab, The process) Ná Disulfida Linkagel E Peptide “i | Figure 7-6 = Pentameric structure of immunoglobulm (loM) pe — 206 Wilson and Gisvold's Texthook of Organic Medicinal and Pharmaceutical Chemistry out, membrane transport systems fail, and the cell dies. This type of reaction yields products that require no special treat- men, ANTIBODY TYPES AND REACTIONS Ab types and reactions are classified on the basis of varia- tions in 4 common section of the Fe fragment that goverms biological activity in a general way. IgG. IgG (Fe = (Fig. 7-5) participates in precipitaton reactions, toxin neutralizations, and complement fixation. IgG is the major (70%) human Ig. The Fab tip fixes antigen, and the Fe fragment can fix complement to yield agglutina- tion or lysis. IgG is the only immunoglobulin that crosses the transplacental barrer and the neonatal stomach, so it provides maternal protection. IgG constitutes about 75% of the total Ab in the circulation, Iris present ata concentration of about 15 mg/mL and has a half-life of 3 weeks. the longest of any of the Ab types. The light chains of IgG can possess either x or À variants. These slight differences in structure are called isorvpes, and the phenomenon is termed isoiypic vertafion. IgM. IgM (Fe = pu (Fig. 7-6) is present at a concentra- tion of about 1,5 mg/ml and has a half-life of less than 1 weck. This Ab participates in opsonization, agelutination reactions, and complement fixation, Opsonization, as stated above, 1s a “protein costing” or tagging of a bacterium that renders it more susceptble to phagocytosis. À complex of the Fe portion of IgM plus C3b of complement is that pro- tein. IgM is the first immunoglobulin formed during immu- nization, but it wanes und gives way to IgG. IgM is a pen- tamer, and its agelutination potency is about 1,000 times that of IgG. IgM is also responsible for the A, B, and O blood groups. The fundamental monomeric TgM structure is much like that of IgG. The pentamer is held together by disulfide bonds and a single 3 (joining) peptide. The affimity of un IgM monamer for antigen is less than that of IgG, but the multimeric structure raises the avidiry of the molecule for an antigen. IgA. IgA (Fe = e) (Fig, 7-9) is found in exocrine gland secretions (milk, saliva, tears), where it protects mucous membranes (e,g., in the respiratory tract). Mis present im the serum as 4 monomer at à concentranon of | to 2 mg/ml, but humans secrete about 1 g of the dimer per day in the mucosal fluids, Secretory IgA consists of two 1gG-like units linked together ut the Fe regions by a peptide known as the secretory frmgment and a J fragment, The secretory fragment 4 Protein a Ee Membrane Transport Receptor Figure 7-9 = Structure of immunoglobulin A (IgA), the mu- cosal Ab that protects the Gl tract and the respiratory mucosa is actually part of the membrane receptor for IgA. The IgA molecule on the mucosal side of the membrane binds anti gen, then binds to the receptor. By a process of transcytosis, the IgA-antigen complex is moved from the mucosa to the bloodstream, where IgG and IgM can resct. Because dl is distributed on the mucosa. IgA has an anatomically specific distribution, unlike the other antibodies. IgA is the mediator of oral polio vaccination (the mucosal reaction gives way lo systemic protection). IgD. IgD (Fe = 5) is present on the surface of B cells and, along with monomenric surface IgM, 1s an antigen recep- tor that achivates immunoglobulin production. There 15 less than 0.1 mg/ml in the bloodstream, and the half-life is only 3 days. IgE. IgE (Fc = ejis the Ab responsible for hypersensk tivity reactions, IgE complexes have a high affinity for hos cell surfaçes and can damage the host. High levels of Igê are found in persons with allergies of various types, as well) as in autoimmune diseases. The Fe fragment is responsible for the Ig=cell reactivity. An Ab-plus-antigen reaction vichde lhe typical Ab-antigen complex. The Fe portion of the Ab is actually par of the mast cell. When antigen binds to dha Fah portion of the Ab, the IgE molecules become cros linked. This probably distoris the membrane of the ma cells and stimulates them to release histamine, which cause bronchial constricton, itching, redness, and anaphylaxis ACQUISITION OF IMMUNITY Several types 0f immunity must be considered when de ing vaccines and other immunobiologicals. Some are am cial and some are natural. Natural immuntty is endowed phagocytic white blood cells, Iysozyme in tears, the and so on. Acquired immunity às acquired after binh Ra by passage from mother to fetus). Thus, imimunity may classified as e Active acquired imunenitv: The host produçes his or her 08 Ab, * Naturally coquired active immuniry: Occurs on recoverça a disease (or from antigen exposure) s Artificially acquired active Immuniry. Occurs as à res sensitization by a vaccine or toxoid e Passive acquired immuniry: The subject receives Ab fra outside source, such as a qeglobulin injection, or by cental transfer. e Naturally acquired passive immunity: Temporary neo protection from maternal TgG passes to the fetus im uia type 0F immunity is mor long-lasting * Artificially acquired passive immunity: An Ab is pipi injecthon, e.g. by am antitoxin or à eglobulin injectiom Definitions of Immunobiologicalis Immunobiologicals include antigenic substances, SUB vaccines and toxoids, or Ab-containing preparatioas 8 as globulins and antitoxins, from human or animal do These products are used for active or passive immune or therapy, All of the following are examples of inmrim logicals: 1e IgA é Vaccine: A suspension of live (usually attenuated) or inacti- s anti- valed microorganisms (e.g., bacteria, viruses, or nicketisiac) vtosis, or frachons thereof, administered to induce immunity and pre- AD the vent infectious disease or ils sequelae Some vaccines contain eitis ! highly defined antigens, e.p.. the polysaccharide of Haemophi- pecific lies dnflnencae type b €Hib) or the surface antigen of hepatitis B; à olhers have antigens that are complex or incompletely defined, ediator Ego Killed Bordetella pertussis or live altenuated viruses, way to + Toxoid: À modified bacterial toxin that has been made non- toxto but retains the ability to stimulate the formation of anti- terna. B cells * Immune globulin (IG): A sterile solution containing antibodies [recep- from human blood. [tis obtained by cold ethano! fractionation is less pH large pools of blood plasma and contains 15 to 18% protein. : intended for intramuscular administration, O is primarily in- is only Ee Ed à 7 tended for routine maintenance of immunity in certain immu- podeficient persons and for passive immunization against measles and hepatitis A. IG does not transmit hepatitis B virus, =rsensi- human immunodeficiency virus (HIV), or other infectious dis- ior host cases of IgE | é Intrqvenous immune globulin (IGIVI A product derived from as well blood plasma from a donor pool similar to the IG pool but onsible prepared so it is suitable for intravenous use, IGIV does not ' ; transmit infectious discases. Tt is primarily used for replace- nyields Cria a Pq pin the Ab ment erapy in primary Ab deficiency disorders und for e trestment 0! Kawasaki's disease, immune Urombocytopenia s to the púrpura, hypogammaglobulinemia in chronic lymphocytic * Crossa leukemia, and some cases of HIV infection. 1 mast Do Specific immune globulin: Special preparations obtained from 1 causes blood plasma from donor pools preselected lor a high Ab laxis. content against a specific antigen (e.g. hepatitis B immune globulin, varicella=zoster immune globulin, rabies immune globulin, tetanus immune globulin, vaccinia immune globulin, and cytomegalovirus immune globulin), Like IG and IGIV, lhese preparations do not transmit infectious disease, e Antonin: A solution of antibodies (e.g., diphtheria antitoxin od botulinum antitoxin) derived from the serum of animals mmunized with specific antigens. Antitóxins are used to con- fer pússive immunity and for treatment. Wacelnation denotes the physical act of administering a eine or toxoid. Imumunizarion is a more inclusive term moing the process of inducing or providing immunity arti- eully by administering an immunobiological. Immuniza- may be active or passive. ine may be defined as a solution or suspension of lados live/atenuated virus, killed ncketisia, killed or live/ bacteria, or antigens derived from these sources, pare used to confer active, artificially acquired immu- agunst Chat organism or related organisms. When ad- jistered, the vaccine represents the initial exposure, re- in the acquisition of immunity, A subsequent re or challenge (a disease) results in the anamnestic, + Fesponse. ETHODS OF VACCINE PRODUCTION Eme production methods have varied greatly over the ao are best discussed according to a parallel chrono- À and sophistication approach. led (inactivated) Pathogen. In this method, the pomial pathogen is treated with a strong, denaturing disin- Chapter 7 = immunobiologicals 207 fectamt like formaldehyde or phenol. The process denatures the proteins and carbohydrates that are essential for the or- ganism to live and infect a host, but if treated properly, the surface antigens are left intact. The process must be done carefully to control the umwinding of proteins or carbohy- drates by denaturation, since the preparation must be recog- nized as the original antigen, The main problems with Killed pathogen vaccines are: (a) 1 the vaceine is not inactivated totally, disease cam result; (b) if the preparation is over- treated, vaccine failure usually results because of denatur- ation: (c) the production laboratory must grow the pathogen in large quantities to be commercially useful, putting labora- tory technicians at nsk; and (d) the patient may experience abnormal and harmful responses, such as fever, convulsions, and death. These vaccines typically are viewed as “dirty” vaccines, and some, like the pertussis vaccine. have been associated with problems serious enough to warrant their temporary removal from the market Live/Attenuated Pathogens. The word attenuated for our purposes simply means “low virulence.” The true pathogen is altered phenotypically so that it cannot invade the human host and cannot get ahead of the host's immune system. Low-pathogenicity strains such as these were origi- nally obtained by passage of the microbes through many generations of host animals. The idea was that the animal and the pathogen, if both were to survive, needed to adapt to live with cach other without either partner being killed. Poliovirus is attenuated in this fashion in monkey kidney tissue, In a live/attenuated vaccine, antigenicity is still re- quired, as is infectivity (polio vaccine vields an infection), but the hosts immune system must be able to stay ahead of the infection. The key problems are: (a) the vaccine cannot be used if the patient is immunocompromised, has fever or malignancy, or is taking immunosuppressive drugs: (b) these vaccines should not be used during pregnancy; and (e) the attenuated organism commonty reverts to the virulent strain, which was the reason for the failure of some early polio vaccines. Today, biological quality control is very stringent, and these problems have been eliminated. Live/Attenuated Related Strain. The live/attenuated related strain is antigenically related so that it can provide cross-immunity to the pathogen. For example, cowpox virus can be used in place of smallpox virus. The strains are anti- genically similar enough so that the hosts immune system reacis to the related strain to provide protection against the normal pathogen. The main advantage is that a true pathogen is not being used so that the chance of contracting the actual disease is zero, The problem with such vaceines is that they cause an infechon. Cowpox is known to spread to the central nervous system in | in OS cases, causing a potentially fatal form of memngitis, Cellular Antigen From a Pathogen. The surface anti- gen (L.e., what is recognized as foreign) is harvested from the pathogen, purified, and reconstituted into a vaccine preparation. These antigens can take a number of forms, including the carbohydrate capsule, as in Neisseria meningit- idis; pili, as in N. gonorrhoeae: flagella from motile bacteria (the basis for an experimental cholera vaccine); or the viral ali sam my teh vis om ha and Las nted are utch the wuri- com- igem mam vac- wgan- A VR tins of abent). Wolec- he im- o each unisms ven for ve shol RI val ed ae on the vith one a single- . spaced é. Multi= “hich are ter dose. imunizã- se). As o balster nor sus nus). cine does “cine 15d + aqueous accine is te, Like ger Expo he matrix adsorbed Pharmaceutical Principles of Vaccines. As expected fora live biological preparation, heat destroys live viral and iacterial vaccines. If the agent is not killed, the antigen may be ultered. Like many biologicals, Iyophilized vaccines are unstable after reconstitution. Ice crystals formed inside the protein structure during freeze-drying expand during thaw- ing and disrupt the structure of the vaccine, Live vaccines can be inactivated by minute amounts of detergent. Deter- pent residue adhering to glassware is concentrated enough to metas a disinfectant, lt is safe to use only plastic implements specified for the vaccine. The suspending medium may be slerile water, saline, or more complex systems containing protein or other constituents derived from the medium in which lhe vaccine is produced (e.g., serum proteins, egg antigens, and cell culture-derived antigens). Concentrated Ab suspensions (7-globulins) are typical amphiphilic pro- eins and aggregate on storage. IH injected, the particulates may cause anaphylaxis. Preservatives may be components dl vaccines, antitoxins, and globulins. These components are presentto inhibit or prevent bacterial growth in viral cultures oribe final product or to stabilize the antigens or antibodies. Allergic reactions can occur if the recipient is sensitive to mat of these additives (e.g.. mercurial compounds [thimero- sul), phenols, albumin, glycine, or neomyein). Storage and Handling of Immunabiologicals. Fail- gre to follow the exact recommendations for storage and fundling of immunobiologicals can lead to an impotent preparation. During reconstituting, storing, and handling of immunobiologicals. the most important recommendation is jofollow the package insert exactly. Vaccines should always he stored ut their recommended temperature, Certain vac- nes, such as polio vaccine, are sensitive to increased tém- perature. Other vaccines, such as oral polio vaccine, diphihe- Ha and tetanus toxoids, and acellular pertussis vaccine, hepatitis B vaccine, influenza vaccine, and Hib conjugate qaccine (Hib-CV) (among others), are sensitive to freezing. Viral Vaccines"? SMALLPOX VACCINE (DRYVAX) Smalipox vaccine is live vaccinia (cowpox) virus grown om fe skin of a bovine calf. Smallpox is a highly lethal and Esfiguring disease that was common throughout history. Smalipox vaccine was used routinely in the United States hat today is no longer recommended. (There have been no mported cases of smallpox since the 19405.) In 1982, small- pos was declared eradicated worldwide, With smallpox, the quks of the vaccine outweigh the benefits; the vaccine pene- jutes the central nervous system and potentially fatal en- gephalitis occurs in | in 10" patients. After exposure to “malipox. the vaccine can be injected to lessen the severity Wlihe discase. FNFLUENZA VACCINE" 14 15. 18,17 hflvensa vaccine is a multivalent inactivated influenza virus Bee viral subunits (split vaccine). The virus is grown on chick “embryo and inactivated by exposure to ultraviolet (UV) light formaldehyde. The antigen type is protein, The vaccine he United States contains lhimerosal, a mercurial, as a peervative. Influenza is a respiratory tract infection with a 209 Chapter 7/8 Immiunobiologicals 2-day incubation period. The disease may be devastating and can lead to pneumonia. Wilhout the vaccine, influenza 15 common in epidemics and pandemies. To clarify, the flu is a Gl infection with diarrhea and vomiting. Influenza requires wecks of incubation. Influenza is caused by two main genetic strains cach year (A and B): type A is most common in humans; type B is less common. The virus mutates very rapidly, and vaccines must be tailored yearly, The World Health Organization (WHO) and the Centers for Disease Control and Prevention (CDC) monitor the migration of the disease from Southeast Asia. type the strains causing the occurrences, and order a vaccine to counter the organisms most likely to enter the United States. Influenza À viruses are categorized according to two cell surface protein antigens bemagglutinin (H) and neuraminidase (N). Each of these is divided further into subtypes (HI. H2; NL, N2). Individual strains within a subtype are named for the location, isolation sequence number, and year of isolation (e.g., A/Beijing/2/ 90 [HIN 1). For example, the WHO-recommended formula for 2001 to 2002 included the following antigens: A/New Caledonia/20/99 (HINT), A/Moscow/10/99 (H3N2), B/51- chuan/379/09, 15 ug cach per 0.5 mL. A typical vaccine will be a mixture of three strains. Strains are selected cach year in the spring on the basis of the discase trends observed and are released in the autumn. In general, those patients who are at high risk for complications from influenza are * Persons 65 vears of age or older e Residents of nursing homes and other chronie-care facilitics that house persons of any age who have chronic medical condi- tions e Adults and children who have chronic disorders of the pulmo mary or cardiovascular systems, including asthma e Adulis and children who have required medical follow-up or hospilalization during the preceding year because of chronic metabolic diseases (including diabetes mellitus), renal dys- function, hemoglobinopathies, or immunosuppresston CGnelud- ing immunosuppression caused by medications or HIV infee- tion) e Children and teenagers (aged 6 months to 18 years) who are receiving long-term aspírin therapv and, therefore, might be at risk for developing Reve's syndrome after influenza infection * Women who will be in the second or third trimester of preg- nancy during the influenza seasom e Health care workers and those in close contact wilh persons at high risk, including household members e Housechold members (including children) of persons in groups at high risk, including persons with pulmonary disorders, such as asthma, and health care workers who are at higher risk because of close contact LU is impossible to contract influenza from the vaccine, The only side effects may be local pain and tenderness at the injection site, with low-grade fever in 3 to 5% of patients. Aspirin and acetaminophen are effective in combating these symptoms. Allergie reactions are rare but may be seen in persons allergic to eggs. Immunity to influenza vaccine takes 2 weeks to develop. Some people fear the vaccine because of reports of a strange paralvsis and lack of nerve sensation associated with the 1976 swine flu vaccine, This problem, Guillain-Barré syndrome, was associated only with this 1976 vaccine and has not been associated with vaccines since." 210 POLIO VACCINES 89-20 Polio is a dangerous viral infection that affecis both muscle mass and the spinal cord. Some children and adults who contract polio become paralyzed, and some may die due to respiratory paralysis. Polio was the cause of the “infantile paralysis” cpidemic of 1950 to 1953, which led to many paralyzed children and the specter of patients spending their lives in an iron lung. Serious cases of polio cause muscle pain and may make movement of the legs and/or arms diffi- cult or impossible and, as stated above, may make breathing difficult Milder cases last a few days and may cause fever, sore ihroat, headache, and nausea. Interest in polio has in- creased because of recent local outbreaks; large numbers of people are unimmunized. There are no drugs or special therapies to cure polio; treatment is only supportive. The symptoms of polio may reappear 40 to 50 years after a severe infection, This phenomenon is known as postpolio muscle atrophy (PPMA). PPMA is not a reinfection or reactivation of the virus but is probably a form of rapid aging in polio survivors. There are two types of polio vaccines. Inactivated Polio Vaccine (IPV). There are several syn- onvyms for the IPV vaccine: TPV, e-IPV, ep-IPV, and the Salk vaccine (1954 [IPOL, Aventis-Pasteur|). e-APV is an enhanced porency poliovirus, more potent and immunogenie than any of the previous IPV formulations. e-IPV is recom- mended for all four infant doses because of the incidence of rare cases of oral polio vaccine (OPV j-associated paralytic poliomyelitis. e-IPV is also preferred for adults for the same reason. IPV is a trivalent (strains |, 2, 3) vaccine grown im monkey kidney culture and subjected to elaborate precau- tons to ensure inactivation (typically, formaldehyde is used). The antigen form is whole virus. The antigen type is protein. The vaccine is injected to cause induction of active sustemic immunity from polio but does not stop polio car- rers, who shed the virus from the oral and nasal cavities. Trivalent Oral Polio Vaccine (TOPV). TOPV (Sabin vaccine, 1960) is à live attenuated whole virus vaccine (anti- gen type, protein) containing polio strains |, 2, and 3. The virus culture is grown on monkey kidney issue with use of an elaborate attenvation protocol. Oral administration of the vaccine yields a local GI infection. and the initial immune response is via IgA (mucosal, local to the GH tract). The IsA-antigen complex undergoes transcytosis across the mu- cosal membrane, and systemic imemunity is induced as TeM and IgG form. A major caution with TOPV is that it is a live vaccine and must never be injected. Indications are e Mass vaccination campaigns to control outhreaks of paralytic polio e Unvaccinated children who will travel im less than 4 wecks to areas where polio is endemic. e Children of parents who do not accept the recommended num- ber 0F vaceino injecttons. These children may receive OPV only for the third or fourih dose or both. In such cases, the health care provider should admimister OPV only after discus- sing te risk of OPV -associated paralytic poliomyelitis with parents or curepivers e c-JPV is recommended for routine use tm all four immunizing doses im infants and children Wilson and Gisvold's Tedbook of Organic Medicinal and Pharmacentical Chemistry * The WHO has advocated giving children e-APV instead of TOPY to prevent exposure of others to virus shed through the nose and mouth? * RUBELLA VACCINE?' German measles is a disease thai was once called the **3-day measles"”” and was considered a normal childhood illness. If is a mild discase with few consequences, except in the fist trimester of pregnancy. In these mothers, rubella causes birth defects in 50% of cases. Defects may include heart discase, deafness, blindness, leaming disorders, and spontaneúus abortion of the fetus. Symptoms of rubella are a low-grade fever, swollen neck glands, and a rash that lasts for about 3 days. About 1 of every 10 women of childbearing age in the United States is not protected against rubella. Also, 20% of all adults escaped this normal childhood disease or are not vaccinated. Rubella vaccine (German measles vaccine, live, Meruvar H. Merck) is a live, attenuated rubella virus produced in human diploid cell culture. The antigen form of the vaccine is whole virus. The antigen type is protein. The vaccine | administered as part of the normal immunization schedule ut 15 months. Side effects are minimal, but there may be some soreness und pain at the site of injection and stiffness of the joints. A problem with the vaccine is that administration of a live virus is contraindicated in pregnancy. Indications are e Persons aged 12 months to puberty should be immunized pot tinely * Previously unimmunized children of susceptible pregnant women should receive the MMR vaccine. The trivalent va eme às preferred for persons likely to be susceptible to mumps and rubella * Immunization of susceptible nonpregnant adolescent or aduk women of childbearing potential às called for if precautions to avoid pregnancy are observed * Almost all children and some adulis require more than om dose of MMR vaccine e On the fist routine visit to he obstetrician-gynecologist, He immune status should be checked, 1 the woman ds not tmn mized against rubella, the physician should administer the vao: cine und stress avoiding pregnancy for 3 months e Tí the patient is already pregnant, the physician should not administer the vaccine e If exposure is suspected, lhe cond blood should be monitores for the presence of rubella antibodies. “A unimmunized women should be vaceinated immediately after delivery of the baby MEASLES VACCINE (ATTENUVAX, MERCK)! Measles is a very serious, highly contagious discase, causes à high fever, rash, and a cough lasting | to 2 wecks Some patients experience extreme sensitivity to light. The rash may occur inside the eyelids. producing a very painful condition. In the United States, between 3,000 and 28,000 cases occur cach year, depending on factors such as weather and localized outbreaks, Outbreaks are very common in neighborhoods and schools. One of 10 children contracting measles will develop an car infection or preumônia. Measles may infect the brain (encephalitis) and lead to convulsions, hearing loss, and mental disability. In the United States, | of every 500 to 10,000 children comracting measles dies Wilson and Gisvold's Textbook of Organie Medicinal and Pharmaceutical Chemistry 212 TABLE 7-6 Recommended Childhood Immunization Schedule—United States January to December 2000 Age ' : 1 2 , 8 2 |15 | 18 | 2 | 4-6 |41-42 |14-16 Vaccine Birth | mo mos | mos | mos| mos | mos | mos | mos | yrss yrs yrs Hepatíris E” Hep B Hep B Hep 8) biptitheria att á | T + ul mu parta O DraP |DTaP |DTaP DTaP fra H influenzas type " Hib Hib [Hib Hib MPR PV JIPV PV IPV Meme des-mumpas- rula MMR MR) Hap À in solocted areas Varicelta é é 0É recommended ages for vaccinanion = Vaccines to be given tl previous)y recommended doses were missed ot were given eurlier than the recommended minimum age Recommend 1999, the Advisory Commitico on Imimunization Practices (ACIP) recommanded that Rotashield [rhesus rotuvirus vaccine-tetravalent (RRW-TV)] the one he United States (MN WR, Vol, 48, No. 43, November 6, 1999) Parents should be reassured thar children wiro meceivel Cd nisk for intussusception q and/or regions. dim seleched st On Ocioher USelicensed rotavirs vaccir ser be used im E a dr trus vaccine, no | before July 1999 This schedule indicares the recommended ages for routine adminisiration of licensed childhood vaccines as of November |, 1999, Any dose not given at the recommended aeh-up” vaccination at any subsequent visit when indicated and feasible, Additional vaccines may be licensed and recommended during the ear Lie vidders should com alnealed es prvi cas dá combination vstoines may be used whenever any components of the combination are indicated and the vaçeine's other components are not contraindicared. P) sult tho manutfaçiurcos” package inserts for demiled recommendations. Enfanis born to hepatítis À surface antigen (HESA phnegative mothers should receive the first dose of hepatitis B vaccine (Hep By by age 2 months, The second dose choulê be actministered at leade | month after the First dose. The thind dose should be administered at least 4 months after the first dose and at least 2 months after the second dose, but not before age 6 momiha. infants horn to HRsAg-positive mothers should receive Hep B and 0.5 ml. heparitis À immune plobulin CHRIG) venham 12 houes of birth at separate sites The second dose bs recommended atage 1-2 months, amd the third dose at age 6 monthe. Infants bora to mothers whose HBsAg status |s unknown should receive Hep B withia 12 hours of birth. Maternal blood should be drmwn at delivery to determine the mother's HBsÃp status, df the HBSÃg test te positive, the infant should receive HBIG as soon a possible (no later than E week) Al chitdren and adolescents (through age 18 years) who have not beem vaccinated against hepatitis B may begin the series during amy vid Prospidhers sbrvale! male special elforts to vaccine children who were bom in or whose parents were bom in areas of the word were hepatitis B virus infection is moderabely ce highly endeémio “The fourth dose of diphihera and tetanus toxobds and acelular perussis vaccine (DTaP) con be adminigered as carly as age 12 months, provided 6 months have clapsed simer e 15-18 months. Tetunas and dipitheria tolas (Td) are recommended atage 11-12 years ia least years have elapsed since the last dose of diphihe À tetanos toxoids and perussis vaccine (E'TP), DTaP, or diplhitheria and tetanus toxoids (DT). Subseguent routine Td boosters are recommended evers e vaccine (PRP-OMP) (Ped vaxHIB or ComVax [Merck j às admeinho E some combinalhom products my pe gate vaccines are hcensed for infant use. JF Hib comju; age 6 months às not required. Because clinical studies tn infants have demonstrated that si ine component, Dra/Hib combination products should no be used for primary vaccination in infamis at ages 2, 4, 00 6 months unless 2 monihs and d months, a dose s duce a lover immune response to the Hib vo approved by the Food and Drug Administration for these ages “To eliminate the msk for vaccine-associated paralytic poliompelitis (VAPP). an all-inactivated polioviras vaccine (PV? schedule às now recommended for routine childial polo vaceinatioa intho United States: All children should receive four doses of PV; at age 2 months, age 4 months, benween ages 6 and 18 months, amd between aged and b É (OPW) (E availal 1y be used only for the following special circumsances: 1) mass vaccination campaigns to control oulbreaks-of paralyile po Le traveling in
