The Immune System 4th Edition Parham Test Bank
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THE IMMUNE SYSTEM, FOURTH EDITION
CHAPTER 11: IMMUNOLOGICAL MEMORY AND VACCINATION
© Garland Science 2015
11–1 Give four reasons why secondary immune responses are faster and more effective than primary immune responses.
11–2 Explain (A) why only memory B cells, and not naive B cells, participate in secondary immune responses to particular pathogens, and (B) why this is advantageous to the host.
11–3 Explain briefly how immunological memory operates in (A) the short term and (B) the long term.
11–4 Which of the following statements is incorrect regarding memory B cells?
- Memory B cells are maintained for life.
- In secondary responses, the number of pathogen-specific B cells is about 10–100-fold that seen in primary responses.
- The sensitivity of memory B cells is improved compared with naive B bells because affinity maturation has occurred.
- Memory B cells express lower levels of MHC class II and B7 than do naive B cells.
- Memory B cells differentiate into plasma cells more rapidly than do naive B cells.
11–5 Which of the following characterizes immunological memory? (Select all that apply.)
- The host retains the capacity to mount a secondary immune response.
- The host retains the ability to respond to pathogen many years after primary exposure.
- Naive T cells are activated more quickly when exposed to pathogen.
- Memory B cells produce higher-affinity antibody than naive B cells.
- Memory T cells undergo somatic hypermutation.
- Memory T cells express CD45RA.
11–6 What would be the outcome if a naive B cell were to bind to pathogen coated with specific antibody made by an effector B cell in a primary immune response using FcγRIIB1, and simultaneously bind to the same pathogen using its B-cell receptor?
- a positive signal leading to the production of low-affinity IgM antibodies
- a positive signal leading to isotype switching and the production of IgG, IgA, or IgE antibodies
- a positive signal leading to somatic hypermutation and the production of high-affinity IgM antibodies
- a negative signal leading to inhibition of the production of low-affinity IgM antibodies
- a negative signal leading to apoptosis.
11–7 Which of the following explains why the first baby born to a RhD– mother and a RhD+ father does not develop hemolytic disease of the newborn?
- Fetal erythrocytes do not cross the placenta and therefore do not stimulate an antibody response.
- The antibodies made by the RhD– mother during the first pregnancy are predominantly IgM and have low affinity for the Rhesus antigen.
- Maternal macrophages in the placenta bind to anti-Rhesus antibodies and prevent their transfer to the fetus.
- Hemolytic disease of the newborn is a T-cell-mediated disease and maternal T cells do not cross the placenta during pregnancy.
- The Rhesus antigen is not immunogenic and does not stimulate an antibody response.
11–8 By which process are fetal erythrocytes destroyed in hemolytic anemia of the newborn?
- lysis of erythrocytes by cytotoxic T cells
- lysis of erythrocytes by complement activation
- clearance of antibody-coated erythrocytes by macrophages in the fetal spleen
- lysis of erythrocytes by NK cells via antibody-dependent cell-mediated cytotoxicity
- cytotoxicity caused by major basic protein released from eosinophils.
11–9 When a naive B cell binds to an IgG:antigen complex on its cell surface using FcγRIIB1, while simultaneously binding to the same antigen using membrane-bound IgM, _____.
- the IgG:antigen complex is endocytosed
- the B cell becomes anergic
- the B cell will switch isotype to IgG
- the B cell undergoes affinity maturation
- the B cell secretes large amounts of IgM before becoming a memory B cell.
11–10 “Original antigenic sin” is best described as a phenomenon in which _____.
- a highly mutable virus gradually escapes from immunological memory and interferes with compensatory immune responses.
- latent viruses periodically activate effector T cells specific for the original antigen recognized in the primary immune response.
- the persistence of antigen is necessary to sustain maintenance of immunological memory.
- memory T cells no longer express the same profile of adhesion molecules and cytokine receptors compared with the original profile of the naive precursor T cell.
11–11 Imagine a situation in which an individual who has a latent cytomegalovirus (CMV) infection receives a hematopoietic stem-cell transplant. Which of the following is likely to occur?
- The memory T cells present at the time of transplantation would inhibit activation of newly generated naive T cells.
- The CMV viral load would increase exponentially, overcoming the host and causing death.
- The transplant-derived naive T cells would be activated and give rise to memory T cells that would persist and control viral load.
- There would be a rapid increase in CMV viral load and expansion of T cells bearing CD45RA.
11–12 Which of the following are not a component of immunological memory?
- effector B cells
- memory T cells
- memory B cells
- long-lived plasma cells.
11–13 Identify three reasons why memory B cells respond more forcefully and effectively during secondary immune responses than naive B cells during primary immune responses.
11–14 The efficiency and specificity of adaptive immune defenses and immunological memory improve each time a particular pathogen is encountered because _____.
- of protective immunity
- effector memory T cells outnumber central memory T cells
- the half-life of antibodies made in secondary and tertiary immune responses exceeds that of antibodies made in primary immune responses.
- of affinity maturation.
11–15 Unlike naive lymphocytes, memory lymphocytes _____.
- do not recirculate between the blood and secondary lymphoid organs
- do not require the receipt of survival signals through their antigen receptors in order to persist
- are immortal and continue to divide throughout the lifetime of an individual
- secrete antibody continuously, although at a much lower rate than plasma cells
- do not express CD27.
11–16 All of the following are ways in which plasma cells differ from memory cells except _____.
- plasma cells lack surface immunoglobulin
- cellular morphology
- plasma cells are CD27-negative
- plasma cells have undergone isotype switching
- plasma cells are short-lived.
11–17 During a secondary immune response, high-affinity IgG antibodies are produced. Which of the following best explains why low-affinity IgM antibodies are not made?
- Naive pathogen-specific B cells are suppressed by negative signaling through FcγRIIB1.
- Naive pathogen-specific B cells isotype switch and hypermutate much more quickly during secondary immune responses.
- Memory B cells outnumber naive B cells.
- Low-affinity IgM antibodies are made only when antigen concentration is exceedingly high.
11–18 Which of the following molecules is not elevated on the surface of memory B cells compared with naive B cells?
- MHC class II molecules
- antigen receptor
- co-stimulatory molecules.
11–19 Explain why memory B cells are more efficient at responding to pathogens than are naive B cells.
11–20 _____ accounts for the production of different isoforms of the CD45 protein observed in naive, effector, and memory T cells.
- Isotype switching
- Affinity maturation
- Alternative splicing
- Somatic hypermutation
- Recirculation to peripheral tissues.
11–21 Memory B cells differ from memory T cells in the following ways. (Select all that apply.)
- They suppress naive antigen-specific lymphocytes during secondary immune responses.
- They recirculate only through secondary lymphoid organs.
- They secrete their antigen receptors throughout their life-span.
- They generate long-lived clones of memory cells during the primary immune response.
11–22 RhoGAM is administered to pregnant RhD– women so as to _____. (Select all that apply.)
- stimulate only anti-RhD IgM antibody
- cause selective removal of anti-RhD memory B cells from the maternal circulation
- inhibit a primary immune response to RhD antigen
- block transcytosis of IgG to fetal circulation by interfering with FcRn function
- prevent hemolytic anemia of the newborn
11–23 Identify three characteristics of smallpox that aided in the global eradication of this disease through a rigorous vaccination program.
11–24 Identify the mismatched pair. (Select all that apply.)
- variolation: smallpox
- Salk vaccine: killed poliovirus
- vaccinia virus: cowpox
- rotavirus: segmented DNA virus
- Sabin vaccine: TVOP
- rabies vaccine: live attenuated vaccine.
11–25 Recombinant DNA technology has been especially useful for the production of _____ that are used in subunit vaccines.
- viral proteins
- viral nucleic acids
- mutated viruses
- viral polysaccharides
- infectious particles.
11–26 With reference to RotaTaq, identify the incorrect statement. (Select all that apply.)
- It is an attenuated vaccine derived from a human rotavirus.
- It has been genetically engineered to express a variety of human VP4 and VP7 glycoproteins.
- It is a mixture of five cattle rotaviruses.
- It is nonpathogenic in humans unless a genetic reversion occurs.
- Standard tissue culture methods are used for its production.
- It took decades of research to develop this vaccine to an adequate standard.
11–27 Which of the following is an example of a subunit vaccine? (Select all that apply.)
- hepatitis B vaccine
- Bacille Calmette–Guérin (BCG) vaccine
- trivalent oral polio vaccine
- influenza vaccine
- Explain the challenges associated with generating effective vaccines against encapsulated bacteria.
- How have these challenges been overcome?
- Explain the cellular events required for the production of protective IgG antibodies against bacterial polysaccharide components and the development of memory.
11–29 All of the following are examples of adjuvants except _____.
- inactivated Bordetella pertussis
11–30 Explain why the DTP vaccine stimulates a much stronger protective immunity than does the DT vaccine.
11–31 A newly identified antigen protein of Neisseria meningitidis called fHbp increases virulence by _____.
- interfering with the alternative pathway of complement activation
- binding to host-derived heparin
- increasing the adhesiveness of the bacterium
- inhibiting phagocytosis
- inducing inflammation.
11–32 _____ is the approach that mines a pathogen’s genome to reveal potential antigens and derives clues about cellular location, function, and ability to stimulate protective antibodies based on nucleotide sequence.
- Reverse vaccinology
- Herd immunity
11–33 The reason that vaccines against influenza must be administered annually, unlike vaccines against measles, is _____.
- the antigens that stimulate protection against influenza virus are inside the virion and not on the surface
- influenza is an RNA virus with a higher mutation rate
- influenza stimulates T-independent responses that fail to generate memory cells
- the polysaccharide antigens of influenza stimulate poor immune responses.
11–34 When a subpopulation of unvaccinated individuals are protected against a pathogen because the vast majority of individuals in the overall population are vaccinated, this is called _____.
- reverse vaccinology
- subunit vaccination
- partial immunization
- combined immunity
- herd immunity.
11–35 After a campus outbreak of Neisseria meningitidis (meningococcal serogroup B), a devastating bacterial disease, which affected at least eight students at Princeton University, the US Food and Drug Administration approved the use of Bexsero to prevent the development of additional cases on that campus. Bexsero is considered to provide broader protective coverage than the US-licenced vaccines conventionally used against this disease. Which of the following methodologies was used to develop Bexsero?
- conjugation of neisserial capsular polysaccharide to tetanus toxoid
- reverse vaccinology
- formalin treatment of secreted toxins
- production of a combination vaccine that includes DTP plus a meningococcal polysaccharide diphtheria toxoid conjugate
- engineering a nonpathogenic cattle strain of N. meningitidis to express antigens associated with pathogenic human strains.
11–36 Explain why the suppression of naive B cells in secondary immune responses is advantageous for fighting the measles virus but disadvantageous for fighting the influenza virus.
11–37 Differentiate between the following types of vaccine and give an example of each: (A) inactivated virus vaccines; (B) live-attenuated virus vaccines; (C) subunit vaccines; (D) toxoid vaccines; (E) conjugate vaccines; and (F) combination vaccines.
11–38 What risks are associated with live-attenuated virus vaccines?
11–39 Bacterial vaccines differ from viral vaccines in that only in bacterial vaccines are _____ used. (Select all that apply.)
- subunit components
- whole infectious components
- capsular polysaccharides
- capsule:carrier protein conjugates.
11–40 Reasons complicating the development of vaccines to combat chronic diseases include _____. (Select all that apply.)
- evasion of the host’s immune system by the pathogen
- the polymorphic diversity of MHC class I and class II molecules
- the generation of inappropriate immune responses that do not eradicate the pathogen
- survival of the infectious agent for long periods inside the host
- high mutation rates in the pathogen.
- What is the risk to a population that reduces its use of particular vaccines over a period?
- Identify two cases in which this has happened and the underlying reason for distrust in the benefit of the vaccine.
- Explain the difference between the Rotarix and the RotaTeq vaccines used to protect against rotavirus infections.
- Which vaccine provides broader protection?
- Why is this important?
11–43 Why is determining the genome sequences of human pathogens important in the development of new and more effective vaccines?
11–44 On an otherwise uneventful sunny Sunday afternoon, an extremist group enters your city in a large van and drives to the front entrance of the Convention Center where the annual flower show is taking place. The occupants unload large crates resembling flats of assorted flowers, and then drive off. Within minutes the crates explode, showering the visitors with an opaque powder. Medical teams are called to the scene to care for the injured, and CDC officials wearing level 4 containment suits arrive in a few hours to test the contents of the powder for human pathogens using multiplex PCR methodology (a rapid method for identifying pathogens by their DNA). Which of the following potential bioterrorism agents would pose the most serious threat to those exposed?
- Bacillus anthracis (anthrax)
- Corynebacterium diphtheriae toxin (diphtheria)
- Yersinia pestis (plague)
- variola major (smallpox)
- Clostridium botulinum toxin (botulism).
11–45 In which ways do memory B cells active in a secondary immune response differ from the naive B-cell population activated in a primary immune response? (Select all that apply.)
- The antibody produced is of higher affinity in a secondary immune response.
- The frequency of antigen-specific B cells is lower in a secondary immune response.
- The level of somatic hypermutation is higher in a secondary immune response.
- Higher levels of IgM are produced in secondary immune responses.
- B cells do not require T-cell help in secondary immune responses.
- Memory B cells express higher levels of MHC class II molecules.
- Naive B cells express higher levels of co-stimulatory molecules.
11–46 Which of the following explain why infections with influenza virus erode immunological memory over time? (Select all that apply.)
- Influenza is a highly mutable virus that changes its epitope composition.
- A compensatory immune response to new epitope variants is suppressed in naive B cells.
- The antibody response is directed only toward new epitope variants, resulting in a decreased memory response.
- Cross-linking of B-cell receptor and FcγRIIB1 on memory B cells induces anergy.
- Naive B cells are suppressed by cytokines made by memory B cells.
11–47 Naive T cells do not express _____. (Select all that apply.)
11–48 The production of CD45RO results from the removal of _____ during _____ processing.
- domain A; post-translational
- domain A; post-transcriptional
- exons A, B, and C; post-translational
- exons A, B, and C; post-transcriptional
- exon A; post-transcriptional.
11–49 Effector memory cells enter _____, whereas central memory cells enter _____.
- B-cell follicles; T-cell zones of secondary lymphoid tissues
- T-cell zones of secondary lymphoid tissues; B-cell follicles
- secondary lymphoid tissues; primary lymphoid tissues
- T-cell zones of secondary lymphoid tissues; inflamed tissues
- inflamed tissues; T-cell zones of secondary lymphoid tissues.
11–50 Indicate whether each of the following statements is true (T) or false (F).
___ a. Memory T cells can persist in the absence of antigen.
___ b. The CD45RA isoform is associated with stronger signals in response to antigen.
___ c. T-cell survival is dependent on the cytokines IL-7 and IL-15.
___ d. Naive B cells are more sensitive to specific antigen than are memory B cells because they express higher levels of co-stimulatory molecules.
11–51 Fill in the blanks.
- Cross-linking ________ and ________ on a ______ B cell by a specific antigen:IgG complex renders the B cell anergic.
- Treatment based on the above phenomenon is used to prevent hemolytic disease of the newborn, which can occur in families in which the mother is ______ and the father _______.
11–52 _____ involves deliberate stimulation of the immune system and induction of protective immunity to a particular disease-causing pathogen by mimicking infection in the absence of disease.
- Herd immunity.
11–53 Inactivation of viruses for vaccine use can be achieved by _____. (Select all that apply.)
- heat treatment
- formalin treatment.
11–54 An example of a live-attenuated virus vaccine is _____. (Select all that apply.)
- Salk polio vaccine
- measles vaccine
- yellow fever vaccine
- rabies vaccine.
- What is the difference between the Salk and Sabin polio vaccines?
- Which one should be used for an individual who has an immunodeficiency disease, and why?
11–56 In the context of providing protection against smallpox, describe (A) the similarities and (B) the differences between variolation and vaccination. (C) Now explain the mechanisms by which immunization with vaccinia virus provides protection against smallpox.
11–57 An example of an inactivated virus vaccine is _____. (Select all that apply.)
- Sabin polio vaccine
- influenza vaccine
- mumps vaccine
- hepatitis B vaccine
- rabies vaccine.
11–58 For a viral subunit vaccine to be effective, _____. (Select all that apply.)
- B cells must be activated
- cytotoxic T cells must be activated
- neutralizing antibodies must be induced
- CD4 TFH cells must be activated
- NK cells must be activated
- it must be derived from viral surface components.
11–59 Indicate whether each of the following statements is true (T) or false (F).
___ a. The Bacille Calmette–Guérin (BCG) vaccine is commonly used in the United States to provide protection against tuberculosis.
___ b. BCG is a heat-killed strain of bovine Mycobacterium tuberculosis.
___ c. Lipopolysaccharide-deficient Salmonella typhi is used to vaccinate against typhoid fever.
___ d. Capsular polysaccharide vaccines are equally effective in infants and adults, and stimulate strong T-independent antibody responses.
___ e. A state of inflammation impairs effective immune responses to microbial products.
11–60 A conjugate vaccine is one that couples _____ to _____ so as to stimulate T-dependent antibody responses.
- polysaccharide; a protein carrier
- a protein carrier; irradiated DNA
- protein carrier; toxoids
- adjuvant; toxoids
- polysaccharide; filamentous hemagglutinin.
11–61 _____ vaccines are the most effective at evoking memory responses against a virus in an immunized host.
11–62 Which of the following vaccines is least likely to pose a risk in an individual with an immunodeficiency?
- Sabin polio vaccine
- measles vaccine
- hepatitis B vaccine
- vaccinia vaccine
- yellow fever vaccine.
11–63 Approximately one-quarter of individuals infected with hepatitis C _____.
- develop a chronic infection of hepatocytes
- are at risk of developing liver cancer
- experience episodes of liver destruction and regeneration
- require a liver transplant
- mount an effective immune response and eradicate the virus.
11–64 Which of the following explain why the safety standards for vaccines are set higher than those for drugs? (Select all that apply.)
- a. Some vaccines can induce a disease state.
- Vaccines provoke side-effects in otherwise healthy children.
- Vaccines are much more costly to develop and test than most drugs.
- Vaccination programs are targeted at large populations.
- Subunit vaccines can potentially integrate into the host genome and activate host oncogenes, leading to the development of cancer.
11–65 An adjuvant enhances the effectiveness of vaccines by inducing the expression of _____ on ________.
- co-stimulatory molecules; dendritic cells
- CD28; macrophages
- MHC class II molecules; T cells
- T-cell receptor; T cells
- immunoreceptor tyrosine-based activation motifs; dendritic cells.
11–66 B cells are activated by CD4 TH2 cells only if both cell types recognize the same antigen. The same epitope, however, does not need to be shared for recognition.
- Discuss why this characteristic is important in vaccine design.
- Provide an example of a conjugate vaccine used to stimulate the synthesis of IgG antibody against Haemophilus influenzae B polysaccharide.
11–67 Tim Smith, aged 16 years, was hit by a car while riding his motorcycle. At the hospital he showed only minor abrasions and no bone fractures. He was discharged later that day. In the morning he experienced severe abdominal pain and returned to the hospital. Examination revealed tachycardia, low blood pressure, and a weak pulse. He received a blood transfusion without improvement. Laparoscopic surgery confirmed peritoneal hemorrhage due to a ruptured spleen. In addition to a splenectomy, which of the following treatments would be administered?
- plasmapheresis to remove autoantibodies (antibodies generated against self constituents)
- regular intravenous injections of gamma globulin
- vaccination and regular boosters with capsular polysaccharides from pathogenic pneumococcal strains
- booster immunization with DTP (diphtheria toxoid, killed Bordetella pertussis, and tetanus toxoid)
- regular blood transfusions
11–68 Jenny O’Mara was five months pregnant when she stepped on a rusty piece of scrap metal while hauling rotted wood from a dilapidated shed in her garden. The sliver of metal cut through her sneaker and pierced her heel deeply. Her physician gave her a tetanus booster. When Jenny’s baby was born she decided to breastfeed. If the baby’s antibodies were tested for specificity to tetanus 2 months after birth, what would be the expected finding?
- the presence of anti-tetanus toxoid IgA antibodies
- the presence of anti-tetanus toxoid IgM antibodies
- the presence of anti-tetanus toxoid IgG antibodies
- the presence of IgM antibody specific for Clostridium tetani cell-wall components
- the presence of IgG antibody specific for Clostridium tetani cell-wall components.
(i) Memory cells outnumber naive pathogen-specific lymphocytes because they have already gone through clonal selection and proliferation when antigen was encountered previously.
(ii) Memory cells can be activated more quickly than naive lymphocytes.
(iii) Memory cells are not restricted to circulation between the bloodstream and secondary lymphoid organs, but can also enter non-lymphoid tissues and can therefore respond to infections sooner.
(iv) Owing to the molecular processes of somatic hypermutation and isotype switching, immunoglobulins made by memory B cells are of a higher quality and possess constant regions that will direct secreted antibody to the appropriate anatomical locations to combat infection.They will therefore compete more efficiently for antigen than naive lymphocytes and in so doing will inhibit the activation of naive lymphocytes.
- Naive B cells carry the inhibitory Fc receptor FcγRIIB1. Complexes composed of antigen and IgG produced in the primary response, or by reactivated memory cells, cross-link FcγRIIB1 and the B-cell receptor, which suppresses naive B-cell activation. In contrast, memory B cells do not carry this receptor, and so are not inhibited in this way.
- The suppression of naive B cells means that only reactivated memory B cells (which have already undergone isotype switching and somatic hypermutation) make antibodies. Thus all the antibodies made are of high affinity and are primarily of the IgG, IgA, or IgE isotype. Suppression of naive B cells eliminates repetition of the events that took place in the primary immune response, which would, if not inhibited, lead to the production of low-affinity IgM antibodies rather than high-affinity, isotype-switched antibodies that are more effective at removing the pathogen.
- Short-term immunological memory operates shortly after an adaptive immune response has cleared the infection in an individual and while the pathogen is still present in the community. If the individual is re-exposed and reinfected, antibodies generated in the first round of infection can bind immediately to the pathogen, blocking its action by neutralization and mediating its removal and destruction by complement fixation and phagocytosis. In addition, any remaining effector T cells or activated B cells can respond straight away to the presence of antigen. These activities ensure that the infection does not re-establish itself and also generate a fresh supply of antibodies and effector cells.
- Long-term immunological memory is mediated through long-lived memory lymphocytes that are generated in the primary immune response. These are cells that can be rapidly stimulated by re-exposure to the same antigen to produce a strong and effective immune response that rapidly clears the pathogen.
11–5 a, b, d
(i) Memory B cells bearing pathogen-specific immunoglobulin are more numerous than naive B cells.
(ii) Memory B cells are activated more easily than naive B cells.
(iii) Memory B cells have already undergone isotype switching, somatic hypermutation, and affinity maturation.
11–19 During germinal-center reactions, isotype switching, somatic hypermutation, and affinity maturation generate memory B cells with higher-affinity receptors than those of naive B cells. This feature enables memory B cells to bind to pathogen antigens at very early stages of infection when the pathogen population is very small. Memory B cells also differentiate into plasma cells more rapidly than do naive B cells. These two characteristics allow antibody production to occur much sooner than would be the case with naive B cells. Cognate interactions with CD4 TFH cells are also more efficient owing to elevated MHC class II and co-stimulatory molecules on the surface of memory B cells compared with naive B cells.
11–21 a, b
11–22 c, e
(i) The smallpox virus evolves slowly, so the antigenic epitopes encountered in a vaccine are likely to be the same as or very similar to the actual virus if exposed to the virus later in life.
(ii) The vaccine is a live virus administered through the skin, so the immune responses that are induced will closely resemble those provoked by a natural infection and establish long-lived memory B cells and memory T cells.
(iii) Smallpox, unlike other poxviruses, infects only humans. This eliminates the possibility of alternative reservoirs in other animal populations and therefore requires the interruption of only one chain of transmission (namely human-to-human) to impede dissemination.
11–24 d, f
11–26 a, d
11–27 a, e
- Encapsulated bacteria possess a polysaccharide capsule that not only resists phagocytosis but also inhibits the activation of the alternative pathway of complement activation. Vaccines containing purified polysaccharide components induce weak T-cell-independent B-cell responses limited to low-affinity IgM antibodies and no memory B cell production.
- These challenges have been overcome by recognizing the need to activate CD4 TFH cells so that high-affinity, neutralizing IgG antibodies are made after exposure to encapsulated pathogens. Because CD4 TFH cells require peptide epitopes presented by MHC class II molecules, a new class of vaccine, a conjugate vaccine, was designed that enabled this goal to be achieved. By linking the bacterial polysaccharide covalently to a potent IgG-stimulating protein such as the tetanus or diphtheria toxoid, peptide epitopes become available for the activation of CD4 TFH cells.
- First, dendritic cells process the toxoid epitope and activate CD4 T cells, which differentiate into TFH cells. Then naive B cells bearing IgM antibodies specific for the polysaccharide take up the conjugate by receptor-mediated endocytosis. The toxoid epitopes are subsequently presented with MHC class II molecules on the B-cell surface to activated toxoid-specific CD4 TFH. The resulting T cell–B cell cognate interaction provides everything needed for an efficient immune response generating high-affinity, polysaccharide-specific protective IgG antibodies and the establishment of both T-cell memory and B-cell memory.
11–30 The diphtheria (D) and tetanus (T) toxoids are purified proteins that on their own do not stimulate Toll-like receptors or other receptors of the innate immune response. Hence, an inflammatory response is not initiated by the DT vaccine, which consequently results in the failure to initiate an adaptive immune response. When inactivated Bordetella pertussis is added to make the tripartite vaccine (DTP), it efficiently activates the innate immune response by acting as an adjuvant and inducing inflammation. It also provides additional pathogenic antigens to which the host responds.
11–35 Rationale: The correct answer is b. Reverse vaccinology was the novel technique used to develop Bexsero®. The genome of Neisseria meningitidis strain MC58 was used to identify candidate proteins that not only were exposed on the bacterial surface or secreted but were also conserved across many different pathogenic strains. Four such candidate proteins were identified, including factor H binding protein (fHbp); Neisseria heparin-binding antigen (NHBA); neisserial adhesin A (NadA); and porin A (PorA). The vaccine consists of all four components. There are conjugate vaccines available (for example Menactra®), but Bexsero is not a conjugate vaccine. There are no toxoid-only vaccines for meningococcal disease. Finally, there are no known cattle strains of N. meningitidis, which is a strictly human pathogen.
11–36 The measles virus is a relatively invariant pathogen that has little, if any, antigenic change. Antibodies made by memory B cells will be just as effective in a recall response as those made in a primary challenge. In fact, antibodies made in secondary immune responses by memory B cells will be more effective because of isotype switching and somatic hypermutation. In contrast, the influenza virus is highly mutable; as a result, new strains emerge each year bearing new epitopes that have not previously stimulated a primary response. Memory response and the suppression of naive B cells restrict antibody production to only those epitopes shared by the infecting strain and the original strain. Over time, the influenza virus will express only a limited number of epitopes that are able to activate memory B cells, and the new epitopes will lack the capacity to stimulate naive B cells.
- Inactivated virus vaccines are made of virus particles that are not able to replicate because they have been chemically or physically treated (for example by heat) in a way that inactivates the nucleic acid. Examples are Salk polio vaccine, rabies vaccine, and influenza vaccine.
- Live-attenuated virus vaccines are made of viruses that have lost their pathogenicity and ability to reproduce efficiently in human cells through mutations accumulated as a result of growing the virus in non-human cells. Examples are Sabin polio vaccine (oral), measles vaccine, mumps vaccine, yellow fever vaccine, BCG and Salmonella typhi vaccine, and varicella vaccine.
- Subunit vaccines are composed only of particular antigenic pathogen components known to induce protective immune responses. Recombinant DNA technology enables the production of antigenic proteins in the absence of other pathogen gene products. Examples are hepatitis B vaccine and Bexsero vaccine.
- Toxoid vaccines are made from chemically inactivated toxins purified from pathogenic bacteria. Toxin activity is eliminated but antigenic activity is not, so an immune response is generated in the absence of pathological damage. Examples are diphtheria vaccine and tetanus vaccine.
- Conjugate vaccines are made by covalently coupling antigenic polysaccharide found in bacterial capsules to a carrier protein (often a toxoid). This converts the otherwise T-independent bacterial polysaccharide antigen into a T-dependent antigen. T cells respond to an epitope on the protein carrier, whereas B cells respond to epitopes on the polysaccharide portion of the conjugate. This ensures that T-cell help is provided to B cells making anti-capsule antibodies. Examples include vaccines against Neisseria meningitidis, Haemophilus influenzae and Streptococcus pneumoniae.
- Combination vaccines consist of components that stimulate protective immunity against more than one pathogen. DTP (diphtheria, tetanus, pertussis) vaccine is an example.
11–38 Live-attenuated virus vaccines are mutant viruses that can replicate, albeit inefficiently, in human cells, thus simulating conditions of a normal viral infection. The attenuated vaccine strains of virus have been obtained by growing the virus over many generations in non-human cells (for example monkey cells) so that it acquires multiple mutations that allow it to replicate but prevent it from spreading in the human body and causing disease. When introduced into humans as a vaccine, there is a small chance that some or all of the mutations may revert to the original nucleotide sequence, restoring the properties of the virulent strain of the virus. This occurs very rarely with the poliovirus used in the trivalent oral polio vaccine (TVOP) and, now that polio is very rare in the United States, this vaccine is no longer recommended and an inactivated poliovirus vaccine is used instead. The more rounds of replication the vaccine virus undergoes in the human host before being contained by the immune response, the greater is the potential for genetic reversion. This is why individuals who suffer from inherited or acquired immunodeficiencies should never receive live-attenuated virus vaccines.
11–39 b, d, e
11–40 a, b, c, d, e
- As the number of susceptible individuals increases to a particular threshold, herd immunity is no longer effective in protecting individuals who have never been vaccinated. The outcome is the resurgence of the disease and an epidemic.
- (i) A resurgence of whooping cough was documented in Japan between 1975 and 1980. Distrust in the vaccine followed the death of two children who had recently been vaccinated with DTP. (ii) A resurgence of measles was documented in the UK at the turn of the 21st century. Distrust was linked to unsubstantiated claims that the MMR vaccine induced autism in children.
- The Rotarix vaccine is a live–attenuated single human rotavirus strain that expresses the G1 variant of V7 (VP7G1) and the P8 variant of VP4 (VP4P8). Both variable proteins are common in disease-causing strains. The RotaTeq vaccine is a mixture of five different non-pathogenic cattle rotaviruses engineered to express VP4P8 and VP7G1, VP7G2, VP7G3, and VP7G4 variants from common human pathogenic strains, in addition to cattle-specific variable proteins.
- The RotaTeq vaccine protects against a broader range of variable proteins than Rotarix does. Both vaccines stimulate neutralizing antibodies against VP4P8 and VP7G1, but RotaTeq also stimulates antibodies against VP7G2, VP7G3, and VP7G4, providing broader protection against the different naturally occurring rotavirus variants.
- Broader protection is important because there are five naturally occurring variants of rotavirus that cause disease. In addition, rotavirus has the potential of RNA reassortment, as seen in influenza, because the genome is made up of 11 separate double-stranded RNA molecules, providing opportunities for the generation of additional diversity.
11–43 Determination of genome composition enables researchers to understand the life cycle and pathophysiology of the pathogen. This type of information assists with the identification of the types of immune responses that are evoked in the host, including NK-cell, T-cell, and B-cell responses. In addition, armed with specific sequence knowledge, recombinant DNA methodology can be used to engineer attenuated strains, either through site-directed mutagenesis or the deletion of virulence genes.
11–44 Rationale: The correct answer is d. The most serious threat would be posed by the biological agent to which there is no immediate defense or antidote. Antibiotics would be effective against bacterial agents such as Bacillus anthracis and Yersinia pestis, and antitoxin against diphtheria and botulism toxins could be administered to those affected. If the powder contained the smallpox virus, however, the population would be particularly susceptible, because there are no antibiotics available to protect the non-immune population, and vaccination would take time to take effect. Those infected in the initial attack could spread this highly infectious virus, which has severe morbidity and a mortality rate of about 30%.
11–45 a, c, f
11–46 a, b
11–47 a, d, e
11–50 a—T; b—F; c—T; d—F
- B-cell receptor; FcγRIIB1; naive
- RhD–; RhD+
11–53 a, b, e
11–54 c, d
- The Salk polio vaccine is an inactivated virus vaccine, whereas the Sabin polio vaccine is a live-attenuated virus vaccine.
- The Salk vaccine should be used for immunocompromised individuals. Live attenuated vaccines carry a risk of mutational reversion in an immunocompromised host to a more virulent, disease-causing strain. This occurs because the virus is able to replicate at higher levels and acquire a significant number of mutations, some of which may lead to reversion to a pathogenic strain.
- Variolation and vaccination are both procedures used to confer immunological protection against the smallpox virus, variola. They both use live virus and stimulate humoral and cell-mediated immune responses against the smallpox virus.
- Variolation, a method used for only a short period in the 18th and 19th centuries because of the risk of developing smallpox, used dried pustules derived from humans exhibiting relatively mild symptoms of smallpox infection. Vaccination, a safer alternative causing only mild infection, used dried pustules from cows infected with cowpox.
- Vaccinia and variola have some viral surface antigens in common. Some of the antibodies made against cowpox surface antigens during immunization are able to bind to shared surface antigens also expressed on the surface of the smallpox virus. Through neutralization, these anti-cowpox antibodies are able to bind to and prevent the entry of smallpox into host cells if the host is infected naturally with the smallpox virus.
11–57 b, e
11–58 a, c, d, f
11–59 a—F; b—F; c—T; d—F; e—F
11–64 a, b, d
- Many bacteria are surrounded by a polysaccharide capsule. In some cases, antibodies against the capsular polysaccharides give protective immunity against the pathogen. Antibodies produced against polysaccharide antigens are generally restricted to the IgM isotype, because the help needed to switch isotypes to IgG is provided by T cells, which recognize only peptide antigens. Adult humans make effective immune responses to polysaccharides alone and thus can be protected by subunit vaccines made from the capsular polysaccharides of encapsulated bacteria. Their antibody responses are polysaccharide-specific, T-cell independent, and involve antibodies of the IgM isotype. In contrast, children do not make effective immune responses to polysaccharides alone and thus cannot be immunized with such vaccines.
However, if the polysaccharide is conjugated to a protein, peptides from the protein part of the molecule can activate specific TH2 cells. B cells specific for polysaccharide will bind and internalize the whole antigen via their antigen receptors, process it, and then present peptides from the protein part on their surface. T cells specific for these peptides will interact with the B cell, delivering the necessary cytokines (such as IL-4) and the CD40–CD40-ligand signal required for isotype switching. The B cell will then produce IgG anti-polysaccharide antibodies. This type of vaccine can be used to immunize children so as to induce protective anti-polysaccharide antigens.
- A vaccine of this type has been produced against Haemophilus influenzae B (HiBC), which can cause pneumonia and meningitis. The conjugate vaccine is composed of a capsular polysaccharide of H. influenzae conjugated to tetanus or diphtheria toxoid (a protein). The antibody response is polysaccharide-specific, T-cell dependent, and comprises IgG that protects children from the meningitis caused by this microorganism.
11–68 Rationale: The correct answer is c. This is a case of passive immunity provided to the fetus during pregnancy through transplacental transfer of IgG. Only IgG antibodies cross the placenta, with the aid of FcRn, and enter the fetal circulation during pregnancy, providing passive immunity for the newborn for the first 3–6 months, after which antibody levels diminish as a result of catabolism, and IgG must then be made by the infant. The antibody specificity will be against the tetanus toxoid, not cell-wall entities, because the booster vaccine is a subunit vaccine made of toxoid from Clostridium tetani, not whole bacterial cells. Sophie will make IgG anti-toxoid antibodies, not IgA, because of the route of immunization; intramuscular injection would stimulate the production of IgG antibodies. IgA antibody production would require mucosal delivery. Therefore, even though the newborn is breastfeeding and passively receiving IgA antibodies from Sophie, the IgA antibodies will not have specificity for tetanus toxoid.