vaccine protocols, 2nd

Vaccine Protocols Second Edition Edited by Andrew Robinson Michael J. Hudson Martin P. Cranage M E T H O D S I N M O L E C U L A R M E D I C I N E TM Vaccine Protocols Second Edition Edited by Andrew Robinson Michael J. Hudson Martin P. Cranage Overview of Vaccines 1 1 From: Methods in Molecular Medicine, Vol. 87: Vaccine Protocols, 2nd ed. Edited by: A. Robinson, M. J. Hudson, and M. P. Cranage © Humana Press Inc., Totowa, NJ 1 Overview of Vaccines Gordon Ada 1. Patterns of Infectious Processes Most vaccines are designed as a prophylactic measure to stimulate a lasting immune response so that on subsequent exposure to the particular infectious agent, the extent of infection is reduced to such an extent that disease does not occur (1). There is also increasing interest in designing vaccines that may be effective as a therapeutic mea- sure, immunotherapy. There are two contrasting types of infectious processes. 1.1. Intracellular vs Extracellular Patterns Some organisms, including all viruses and some bacteria, are obligate intracellular infectious agents, as they only replicate inside a susceptible cell. Some parasites, such as plasmodia, have intracellular phases as part of their life cycle. In contrast, many bacteria and parasites replicate extracellularly. The immune responses required to con- trol the different patterns of infections may therefore differ. 1.2. Acute vs Persistent Infections In the case of an acute infection, exposure of a naive individual to a sublethal dose of the infectious agent may cause disease, but the immune response generated will clear the infection within a period of days or weeks. Death occurs if the infecting dose is so high that the immune response is qualitatively or quantitatively insufficient to prevent continuing replication of the agent so that the host is overwhelmed. In con- trast, many infections persist for months or years if the process of infection by the agent results in the evasion or subversion of what would normally be an effective immune control reaction(s). Most of the vaccines registered for use in developed countries, and discussed briefly in the next section, are designed to prevent acute human infections. 2 Ada 2. Types of Vaccines Almost all of the vaccines in use today are used against viral or bacterial infections (Table 1). They are mainly of three types—live attenuated agents; inactivated, whole agents; and parts of an agent—subunit, polysaccharides, carbohydrate/conjugate preparations, and toxoids. Table 1 Currently Registered Viral and Bacterial Vaccines Viral Bacterial Live, attenuated Vaccinia (smallpox) BCG Polio (OPV) Salmonella typhi (Ty21a) Yellow fever Measles Mumps Rubella Adeno Varicella Inactivated, whole organism Influenza Vibrio cholerae Rabies Bordetella pertussis Japanese encephalitis Yersinia pestis Hepatitis A Coxiella burnetii Subunit Influenza Borrelia burgdorferi Hepatitis B (Hep B) Salmonella typhi VI B. pertussis (acellular) Carbohydrate Neisseria meningiditis (A, C, Y, W135) Streptococcus pneumoniae Conjugates Haemophilus influenzae, type b Streptococcus pneumoniae Neisseria meningiditis (C) Toxoids Corynebacterium diphtheriae Clostridium tetani Combinations Measles, mumps, rubella (MMR) Diphtheria, tetanus, pertussis whole organism (DTPw) Diphtheria, tetanus, pertussis acellular (DTPa) DTPa, Hib, Hep B Overview of Vaccines 3 2.1. Live, Attenuated Microorganisms Some live viral vaccines are regarded by many as the most successful of all human vaccines (see Subheading 4.), with one or two administrations conferring long-last- ing immunity. Four general approaches to develop such vaccines have been used. 1. One approach, pioneered by Edward Jenner, is to use a virus that is a natural pathogen in another mammalian host as a vaccine in humans. Examples of this approach are the use of cowpox and parainfluenza viruses in humans, and the turkey herpes virus in chickens. More recently, the use of avipox viruses, such as fowlpox and canarypox, which undergo an abortive infection in humans, is being used in humans as vectors of DNA coding for antigens of other infectious agents (2). 2. The polio, measles, and yellow fever vaccines are typical of the second approach. The wild-type viruses are extensively passaged in tissue culture/animal hosts until an accept- able balance is reached between loss of virulence and retention of immunogenicity in humans. 3. Type 2 polio virus is a naturally occurring attenuated strain that has been highly success- ful. More recently, rotavirus strains of low virulence have been recovered from children’s nurseries during epidemics (3). 4. A fourth approach has been to select mutants that will grow at low temperatures but very poorly above 37°C (see Chapter 2). The cold-adapted strains of influenza virus grow at 25°C and have mutations in four of the internal viral genes (4). Such strains were first described in the late 1960s, and have since been used successfully in Russia and have undergone extensive clinical trials in the United States. In contrast to the these successes, bacillus Calmette-Guérin (BCG) for the control of tuberculosis was for many years the only example of a live attenuated bacterial vaccine. Although still widely used in the WHO Expanded Programme of Immuniza- tion (EPI) for infants, it has yielded highly variable results in adult human trials. In general, it has proven more difficult to make highly effective attenuated bacterial vac- cines, but with increasing examples of antibiotic resistance occurring, there is now a greater effort. A general approach is to selectively delete or inactivate part or groups of genes (see ref. 5; Chapter 9). Salmonella strain Ty21a has a faulty galactose metabolism, and strains with other deletions are being made. The latest approach is to sequence the bacterial genome, and this has now been done for many different bacteria (see Chapter 19). Genetic modifications also show promise for complex viruses. Thus, 18 open read- ing frames have been selectively deleted from the Copenhagen strain of vaccinia virus, including six genes involved in nucleotide metabolism, to form a preparation of very low virulence, yet one that retains immunogenicity (6). This approach has also been tried with simian immunodeficiency virus (SIV), first with deletion of the nef gene (7) and more recently with portions (the V2 and V3 loops) of the env gene (8). Live attenuated vaccines have the potential to stimulate a wide range of immune responses that may be effective in preventing or clearing a later infection in most recipients. 4 Ada 2.2. Inactivated Whole Microorganisms Viruses and bacteria can be treated to destroy their infectivity (inactivation) and the product used with varying efficacy as a vaccine (Table 1). Compared to attenuated preparations, inactivated preparations must be given in larger doses and administered more frequently. The viral vaccines are generally effective in preventing disease, and the relatively low efficacy of the influenza viral vaccine is partly the result of the continuing antigenic drift to which this virus is subject (9). In contrast, the only bacte- rial vaccine of this nature still in wide use is the whole-cell pertussis vaccine that is reasonably effective, but has been replaced in many developed countries by the sub- unit (acellular) vaccine in order to avoid the adverse effects attributed to the whole- cell vaccine (10). Inactivated whole vaccines generally induce many of the desirable immune responses, particularly the infectivity-neutralizing antibody. Generally, they do not induce a class I MHC-restricted cytotoxic T-cell response, which has been shown to be the major response required to clear intracellular infections caused by many viruses and some bacteria and parasites. 2.3. Subunit Vaccines The generation of antibody that prevents infection by both intra- and extracellular microorganisms has been regarded as the prime requirement of a vaccine. The epitopes recognized by such antibodies are usually restricted to one or a few proteins or carbo- hydrate moieties that are present at the external surface of the microorganism. Isolation (or synthesis) of such components formed the basis of the first viral and bacterial sub- unit vaccines. Viral vaccines were composed of the influenza surface antigens, the hemagglutinin and neuraminidase, and the hepatitis B-surface antigen (HBsAg). Bac- terial vaccines contain the different oligosaccharide-based preparations from encapsu- lated bacteria (see Chapter 10). In the latter case, immunogenicity was greatly increased, especially for the children under 2 yr of age, by coupling the haptenic moiety (the carbohydrate) to a protein carrier, thereby ensuring the involvement of T-helper (Th) cells in the production of different classes of immunoglobulin (Ig), particularly IgG. This approach has become increasingly more popular in recent years (11,12). The two bacterial toxoids, tetanus, and diphtheria, represent a special situation in which the primary requirement was neutralization of the toxin secreted by the invading bacteria. Whereas this has traditionally been done by treatment with chemicals, it is now being achieved by genetic manipulation (see Chapter 9). HBsAg exists as such in the blood of hepatitis B virus (HBV)-infected people, and infected blood was the source of antigen for the first vaccines. Production of the antigen in yeast cells transfected with DNA coding for this antigen initiated the era of geneti- cally engineered vaccines (13). Up to 17% of adults receiving this vaccine are poor or nonresponders, and this is a result of their genetic make-up and/or their advanced age (14). A second genetically engineered subunit preparation from B. burgdorferi to con- trol lyme disease is now available (15). Overview of Vaccines 5 3. Vaccine Safety All available data concerning the efficacy and safety of candidate vaccines are reviewed by regulatory authorities before registration (see Chapter 22). At that stage, potential safety hazards which occur at a frequency greater than about 1/5,000 doses should have been detected (see Chapter 21). Some undesirable side effects occur at much lower frequencies, which are seen only during immunosurveillance following reg- istration. The Guillain-Barré syndrome occurs after administration of the influenza vac- cine at a frequency of about 1 case per million doses; but following the mass vaccination of people in the United States with the swine influenza vaccine in 1976–1877, the inci- dence was about 1 case/60,000 doses (16). The incidence of encephalopathy after measles infection is about 1 case per 1000 doses, but only 1 case per million doses of measles vaccine (17). In the United States, the use of OPV resulted in about one case of paralysis per million doses of the vaccine, because of reversion to virulence of the type 3 virus strain. The Centers for Disease and Control (CDC) Advisory Committee on Immunization Practices and the American Academy of Pediatrics (AAP) recommended that only the IPV be used in the United States after January 1, 2000 (18). Following successful vaccination campaigns that greatly reduced disease outbreaks, the low levels of undesirable side-effects following vaccination gain notoriety. The evidence bearing on causality and specific adverse health outcomes following vacci- nation against some childhood viral and bacterial diseases, mainly in the United States, has been evaluated by an expert committee of the Institute of Medicine (IOM) (19). The possibility of adverse neurological effects was of particular concern, and evi- dence for these as well as several immunological reactions, such as anaphylaxis and delayed-type hypersensitivity, was examined in detail. In the great majority of cases, there was insufficient evidence to support a causal relationship, and where the data were more persuasive, the risk was considered to be extraordinarily low. Measles has provided an interesting example of vaccine safety. The experience of the WHO EPI shows that the vaccine is very safe (20). Although natural measles infection induces a state of immunosuppression, even immunocompromised children rarely show this effect after vaccination (19). In developing countries, the EPI sched- ule is to give the vaccine at 9 mo of age. This delay is meant to allow a sufficient drop in the level of maternally derived antibody so that the vaccine can take. In some infants, this decay occurs by 6 mo, resulting in many deaths from measles infection in the ensuing 2–3 mo. “High-titer” vaccines were therefore developed, which could be given at 6 mo of age. Trials in several countries showed the apparent safety and efficacy of the new vaccine, but after WHO authorized its wider usage, some young girls in disad- vantaged countries died, leading to the withdrawal of the vaccine (21). One possibility is that the high-titer vaccine caused a degree of immunosuppression sufficient to allow infections by other infectious agents. Even after using great care in developing a vaccine, unexpected effects can occur after the vaccine has been registered for use. A rotavirus vaccine, registered for use in the United States in 1998, was withdrawn in 1999 after administration to 1.5 million 6 Ada children, because of an unacceptable level—about one case per 10,000 recipients in some areas—of the condition intussusception (22). It is particularly difficult to attribute causality to the onset of diseases that may occur many months after vaccination. When such claims are made, national authori- ties or WHO establish expert committees to review the evidence. There have been claims—sometimes in the medical literature but often from anti-vaccination groups— that a vaccine can cause sudden infant death syndrome (SIDS), multiple sclerosis, autism, asthma, or a specific allergy. There is no sound medical, scientific or epide- miological evidence to support these claims. For example, at least eleven different investigations have found no evidence that inflammatory bowel disease and autism occur as a result of measles, mumps, rubella (MMR) vaccination (23,24). 4. Efficacy Many countries keep yearly records of disease incidence and the Centers for Dis- ease Control and Prevention (CDC) in Atlanta have kept records from as early as 1912. The incidence of cases of some common childhood infectious diseases during a major epidemic is compared in Table 2 with the incidence in 1997, some years after the introduction of the vaccine. Although derived in relatively ideal conditions, as all Table 2 Efficacy in the USA of Some Childhood Vaccines a Before vaccination After vaccination Decrease in Number of Vaccine Number of disease Disease agent cases (yr) (yr)* cases (1997) incidence (%) Diphtheria 206,919 (1921) 1942 5 99.99 Measles 894,134 (1941) 1963 135# 99.98 Mumps 152,209 (1971) 1971 612 99.6 Rubella 57,686 (1969) 1971 161 97.9 Pertussis 265,269 (1952) 1952 5519 97.9 Poliomyelitis (paralytic) 21,269 (1952) 1952** 0 100 (total) 57,879 H. influenzae 20,000 (1984) 165 99.2 (Hib) 1984 a As measured by the decrease in incidence of disease some time after the vaccine was introduced compared to the incidence during an epidemic prior to vaccine availability. *Year of introduction of the vaccine. ** IPV, Salk vaccine in 1952; OPV, Sabin vaccine in 1963. # A two-dose schedule for measles vaccination was introduced after an epidemic in 1989–1991. The 135 cases in 1997 were all introduced by visitors to the United States. Data kindly provided by the Centers for Disease Control and Prevention, Atlanta, and Summary of notifiable diseases, United States. 1998; MMWR. 47; no. 53. Overview of Vaccines 7 the infections are acute and each agent shows little (if any) antigenic drift, the data show that vaccines can be extraordinarily effective (20). Equally impressive is the reduced incidence of one infectious disease in the United Kingdom—a 92–95% reduc- tion in toddlers and teenagers respectively, within 12 mo of the introduction in 1999 of a new N. meningiditis C vaccine (see ref. 11; Chapter 21). One of the greatest public health achievements in the twentieth century was the glo- bal eradication of smallpox. Announced to the World Health Assembly (WHA) in 1980, 3 yr after the last case of indigenous smallpox in the world was treated, the goal took 10 yr to achieve after formation of the Special Programme for Smallpox Eradication by WHO (25). Following the successful elimination of indigenous poliomyelitis in the Americas in 1991, the WHA announced the goal of global eradication by the year 2000. The elimination of indigenous poliomyelitis has now also been achieved in the Euro- pean and Western Pacific regions, and global eradication is now planned by 2005 (26). Prevention of transmission of measles infection has been achieved in several smaller countries, including Finland, as well as in the United States and Canada, following the introduction of a two-dose vaccination schedule. Table 3 lists necessary and desirable properties for an infectious disease to be eradi- cated by vaccination. Although the first four factors are critical, the other three factors contribute to the ease or difficulty of the task. If the Smallpox Eradication Programme had failed, it is unlikely that the other eradication programs would have been initiated. 5. Opportunities for Improved and New Vaccines There are over 70 infectious agents—viruses, bacteria, parasites, and fungi—that cause serious disease in humans (27). There are registered vaccines against 25 infec- tious agents (nearly 40 different vaccines) and approx 14 other candidate vaccines have entered or passed phase II clinical trials. Vaccine development is at an earlier Table 3 Necessary and Desirable Factors for an Infectious Disease to be Eradicated by Vaccination Disease Factor Smallpox Poliomyelitis Measles 1. Infection is limited to humans. Yes Yes Yes 2. Only one or a few strains (low antigenic drift). Yes Yes Yes 3. Absence of subclinical/carrier cases. Yes Yes Yes 4. A safe, effective vaccine is available. Yes* Yes* Yes 5. Vaccine is heat-stable. Yes No No 6. Virus is only moderately infectious.** Yes High Very high 7. There is a simple marker of successful vaccination. Yes No No *The levels of side effects after vaccination were/are acceptable at the time. **The level of vaccine coverage to achieve herd immunity and prevent transmission varied from (usually) 80% for smallpox and is about 95% for measles. 8 Ada stage with most of the other viruses and bacteria (28). Table 4 lists some examples of when improved vaccines are required, and other examples of vaccine development at an advanced stage. 6. New Approaches to Vaccine Development 6.1. Anti-Idiotypes The advantages of this approach include the fact that the anti-idiotype should mimic both carbohydrate and peptide-based epitope; and the conformation of the epitope in question. The potential advantages of the former point have disappeared following the recent successes of carbohydrate/protein conjugate vaccines (11,12). The use of this technology may be largely restricted to very special situations, such as identifying the nature of the epitope recognized by very rare antibodies that neutralize a wide spec- trum of human immunodeficiency virus (HIV)-1 primary isolates (29). Table 4 Some Opportunities for Improved and New Vaccines Improved New Viral Japanese encephalitis Corona Polio Cytomegalo Rabies Dengue Measles Epstein-Barr Influenza Hantan Hepatitis C Herpes HIV-1, 2 HTLV Papilloma Parainfluenza Respiratory syncytial Rota Bacterial Cholera Chlamydia M. tuberculosis E. coli H. ducreyi M. leprae N. gonorrhoeae Shigella Others Malaria Filariasis Giardia Schistosomiasis Treponema Overview of Vaccines 9 6.2. Oligo/Polypeptides ( see also Chapter 8) The sequences may contain either B-cell epitopes or T-cell determinants, or both. Sequences containing B-cell epitopes may either be conjugated to carrier proteins, which act as a source of T-helper cell determinants, or assembled in different ways to achieve particular tertiary configurations. Some of the obvious advantages of this approach are that the final product contains the critical components of the antigen and avoids other sequences that may mimic host sequences, and thus potentially induce an autoimmune response. Multiple Antigenic Peptide Systems (MAPS) are more immu- nogenic than individual sequences (30), and the immunogenicity of important “cryp- tic” sequences may sometimes be enhanced by the deletion of other segments (31). New methods of synthesis offer the possibility of more closely mimicking the confor- mational patterns in the original protein. This approach is likely to be applicable, especially for some bacterial and parasitic vaccines. However, the first peptide-based candidate vaccine that underwent efficacy trials in malaria endemic regions yielded disappointing results (32). A preparation composed of polymers of linked peptides from group A streptococcus, which was effective in a mouse model (33), is currently undergoing clinical trials. 6.3. Transfection of Cells with DNA/cDNA Coding for Foreign Antigens This is now a well-established procedure. Three cell types have been used: prokary- otes; lower eukaryotes, mainly yeast; and mammalian cells—either primary cells (e.g., monkey kidney), cell strains (with a finite replicating ability), or cell lines (immortal- ized cells such as Chinese Hamster Ovary cells [CHO]). Each has its own advantages. As a general rule, other bacterial proteins should preferably be made in transfected bacterial cells, and human viral antigens, especially glycoproteins, in mammalian cells, because of the substantial differences in properties, such as post-translational modifi- cations in different cell types. 6.4. Live Viral and Bacterial Vectors Table 5 lists the viruses and bacteria mostly used for this purpose. Of the viruses, the greatest experience has been with vaccinia and its derivatives such as the highly attenuated modified vaccinia virus Ankara (see Chapter 4). These have a wide host range, possess many different promoters, and can accommodate DNA coding for up to 10 average-sized proteins. The avipox viruses, canary and fowlpox, undergo abortive replication in mammals, making them very safe to use as vectors. Adeno (see Chapter 3) and polio viruses, and Salmonella (see Chapter 6) are mainly used for delivery via a mucosal route, although vaccinia and BCG have been administered both orally and intranasally. Making such chimeric vectors has also been an effective way to evaluate the poten- tial role of different cytokines in immune processes (see Chapter 12). Inserting DNA coding for a particular cytokine as well as that for the foreign antigen(s) results in the synthesis and secretion of the cytokine at the site of infection so its maximum effect should be displayed. Thus, IL-4 and IL-12 have been shown to have dominant effects [...]... these constraints, there are also some promising recent developments 9.1 Combination Vaccines Vaccine delivery is a major cost component in vaccination programs Combining vaccines so that three or more can be administered simultaneously results in considerable savings, so there are determined efforts to add further vaccines to DPaT and MMR, such as DPaT-hepatitis B-H influenzae type b There must be... Saunders Co., Philadelphia, PA, pp 987–1005 4 Maassab, H F., Herlocher, M L., and Bryant, M L (1998) Live influenza virus vaccine, in Vaccines, 3rd ed., (Plotkin, S.A and Orenstein, W.A., eds.) W B Saunders Co., Philadelphia, PA, pp 909–927 5 Levine, M M (1998) Typhoid fever vaccines, in Vaccines, 3rd ed., (Plotkin, S A and Orenstein, W A., eds.) W B Saunders Co., Philadelphia, PA, pp 781–814 6 Tartaglia,... Pertussis vaccine, in Vaccines 3rd ed., (Plotkin, S A and Orenstein, W A., eds.) W B Saunders Co., Philadelphia, PA, pp 293–344 11 Ramsay, M E., Andrews, N., Keezmarsk, E B., and Miller, E (2001) Efficacy of meningococcal serogroup C conjugate vaccine in teenagers and toddlers in England Lancet 357, 195–196 12 Lin, F Y C., Ho, V A., Khiem, H B., et al (2001) The efficacy of a Salmonella Vi conjugate vaccine. .. Hilleman, M R (1992) Vaccine perspectives from the vantage of hepatitis B Vaccine Res 1, 1–15 14 Egea, E., Iglesias, A., Salazar, et al (1991) The cellular basis for the lack of antibody response to hepatitis B vaccine in humans J Exp Med., 173, 531–542 15 Keller, D., Koster, F T., Marks, D H., et al (1994) Safety and immunogenicity of a recombinant outer surface protein A Lyme vaccine J Am Med Assoc... influenza vaccine J Epidemiol 119, 841–879 17 Weibel, R E., Casuta, V., Bessor, D E., et al (1998) Acute encephalopathy followed by permanent brain injury or death associated with further attenuated measles vaccines Pediatrics 101, 383–387 18 Levin, A (2000) Vaccines today Ann Intern Med 133, 661–664 19 Stratton, K R., Howe, C J., and Johnston, R B (1994) Adverse events associated with childhood vaccines... against Streptococcus pneumoniae infection Infect Immun 69, 1593–1598 18 Ada Temperature-Sensitive Mutant Vaccines 19 2 Temperature-Sensitive Mutant Vaccines Craig R Pringle 1 Introduction Many live virus vaccines derived by empirical routes exhibit temperature-sensitive (ts) phenotypes The live virus vaccines that have been outstandingly successful in controlling poliomyelitis are the prime example of... system (CNS), while allowing replication to proceed nor- From: Methods in Molecular Medicine, Vol 87: Vaccine Protocols, 2nd ed Edited by: A Robinson, M J Hudson, and M P Cranage © Humana Press Inc., Totowa, NJ 19 20 Pringle mally in the gut Since the restrictive temperature in the case of the poliovirus vaccines is above normal in vivo temperature, it is possible that a mild febrile response following... development of vaccines against disease caused by respiratory syncytial virus (RSV) and parainfluenza virus (PIV) A meeting report of the WHO Programme for Vaccine Development Vaccine 13, 415–421 7 Juhasz, K., Whitehead S S., Bui, P T,, Biggs, J M., Boulanger, C A., Collins, P L., et al (1997) The temperature-sensitive (ts) phenotype of a cold-passaged (cp) live attenuated respiratory syncytial virus vaccine. .. Indications and contraindications for vaccines used in the expanded programme of immunization Bull WHO 62, 357–366 21 Halsey, N A (1993) Increased mortality following high titer measles vaccines: too much of a good thing Pediatr Infect Dis., 12, 462–465 22 Murphy, T.V., Gargiullo, P M., Nassoudi, M S., et al (2001) Intussusception among infants given an oral rotavirus vaccine N Engl J Med., 344, 564–572... (1997) Vaccines, Vaccination and The Immune Response Lippincott-Raven, Philadelphia, PA, pp 1–247 16 Ada 28 Division of Microbiology and Infectious Diseases, National Institutes of Health (2000) The Jordan Report Accelerated Development of Vaccines, pp 1–173 29 Saphire, E O., Parren, P W H I., Pantophlet, R., et al (2001) Crystal structure of a neutralizing human IgG against HIV-1: a template for vaccine . of Vaccines 1 1 From: Methods in Molecular Medicine, Vol. 87: Vaccine Protocols, 2nd ed. Edited by: A. Robinson, M. J. Hudson, and M. P. Cranage © Humana Press Inc., Totowa, NJ 1 Overview of Vaccines Gordon. after the vaccine was introduced compared to the incidence during an epidemic prior to vaccine availability. *Year of introduction of the vaccine. ** IPV, Salk vaccine in 1952; OPV, Sabin vaccine. virus vaccine, in Vaccines, 3rd ed., (Plotkin, S.A. and Orenstein, W.A., eds.) W. B. Saunders Co., Phila- delphia, PA, pp. 909–927. 5. Levine, M. M. (1998). Typhoid fever vaccines, in Vaccines,