key: cord-0042423-wjkcf03l authors: Tselis, Alex; Booss, John title: Viral Vaccines and Antiviral Therapy date: 2003-12-06 journal: Encyclopedia of the Neurological Sciences DOI: 10.1016/b0-12-226870-9/01325-3 sha: 130ae68f2812e680b4d74696479f7d72a8db1e4f doc_id: 42423 cord_uid: wjkcf03l nan as a commission were created to deal with livestock as well as public health problems. Vicq d'Azyr organized the correspondents of the system into an academy of medicine that later was named the Royal Society of Medicine. During its evolution, the society became progressively involved in issues of public health and criticized perceived flaws at the Faculty of Medicine in Paris and shortcomings in the education of medical students. He became the permanent secretary of the organization. His other careers included court physician of the brother of Louis XVI, the Count of Artois. Before and after the revolution, he also attended and became a favorite of Queen Marie Antoinette, who regarded him as ''my philosopher.'' Vicq d'Azyr was active in medical education and well regarded by the public for his efforts in general health projects. His continued interest was anatomy of the nervous system, and he developed a technique of preserving tissue in alcohol. His dissections elaborated nerve fiber tracts. In particular, he noted a pathway of the visual system that extended to the occipital cortex. Similar observations had been made by Baillerger and Gennari. In addition, he described the connections of the mamillary body to the thalamus, or mamillothalamic tract, to which his name was later appended. His Atlas of Anatomy and Physiology contains an outstanding collection of illustrations of the human brain. Vicq d'Azyr's position brought him into contact with prominent people in France and from abroad. Included in the latter category were John Adams and Benjamin Franklin. He and Adams discussed an interchange of French doctors with the Boston College of Physicians. Despite hostilities with England, he established a system for communication with the Royal College of Physicians. Long interested in reform in medicine and medical education, in 1791, under the auspices of the Royal Society of Medicine, he prepared a plan for the postrevolutionary government. This was adopted completely and formed the basis for later regulations dealing with medical practice and the development of hospitals throughout the country. During the final years of his life, the professional, political, and social milieu of Vicq d'Azyr changed significantly. The profession of medicine was deregulated and the Royal Society of Medicine was ultimately suppressed. Many of his friends and associates were executed by the radical government. His relationship to the monarchy placed him in a position of constant danger. Nevertheless, during his multidimensional career he made significant contributions to comparative anatomy. In addition, efforts in public health more than 200 years ago resulted in changes in the French system of health care that have endured to the present. Antiviral drugs, which interfere with the life cycle of the virus in the host, are of much more recent origin. Their use is grounded on knowledge of the details of how viruses infect and damage cells since viruses use the biochemical machinery of the living cell to replicate. The first scientific instance of vaccination against an infectious disease occurred in 1796 when Edward Jenner, drawing on the common knowledge that those with a history of cowpox never developed smallpox, inoculated cowpox material into the skin of young James Phipps, a local boy. When the boy was later inoculated with fully virulent material from a smallpox lesion, no disease resulted. Jenner named this process vaccination, from vacca, the Latin name for cow. This first published experiment in vaccination was preceded by similar empirical procedures in the Orient that were practiced for centuries. Since that time, vaccines have been developed to prevent a wide range of viral diseases (Table 1) . The basic strategy behind vaccination is to present antigens to the immune system in such a way as to stimulate immunity against the fully virulent organism without causing disease. The vaccine antigens (whole attenuated or inactivated virus or protein subunits of virus) are processed in a way similar to that of the wild-type virus. When the vaccine is injected, the virus or viral proteins are taken up by macrophages, processed, and presented to helper T lymphocytes, which then orchestrate the immune response. The immune system is thus primed so that encounter with wild-type virus results in its elimination. Initially, there were two basic methods for making viral strains suitable for vaccines (vaccine strains). In the first, a virus is ''inactivated'' by exposure to chemical or physical agents that would ''kill'' the virus, for example, by denaturing viral proteins important for attachment to and invasion of the cell, so that the virus is rendered noninfectious. Thus, inactivated virus does not replicate. Inactivated vaccines tend to be less reactogenic than attenuated vaccines and have the advantage that they do not revert to a virulent form. The Salk polio vaccine was inactivated by treatment of the virus with formalin. In the second method for making vaccine strains, a virus is ''attenuated'' by serial passage in cells or host tissues from other species, resulting in the production of viral strains that are specifically adapted to the tissues of the other species and therefore less virulent to humans. Thus, such a vaccine virus causes a mild infection and induces immunity against the virulent wild-type virus encountered in nature. These vaccines have the potential disadvantage of reverting to virulent form. An example is the Sabin polio vaccine, in which the three strains of poliovirus were serially passaged through monkey kidney tissue cells. There have been rare cases of reversion of Sabin vaccine strains to virulent form, and a few cases of paralytic poliomyelitis have resulted. There are several other methods of producing vaccines in development, including subunit vaccines, vector vaccines, and DNA vaccines. They are usually given parenterally, and various schedules of administration are used. Subunit vaccines are made by purifying an immunogenic viral protein and incorporating it into a vaccine. Since only the single viral protein is used, there is no danger of inadvertent infection with the virus. An example is the original hepatitis B vaccine, in which hepatitis B surface antigen (HbsAg) was purified from the blood of hepatitis B carriers. This viral protein is now produced by recombinant DNA methods, involving no human blood products. Vector vaccines consist of a relatively nonpathogenic virus incorporating a gene, from a virulent virus, which encodes antigenic protein. The strategy is that during the mild infection by the vector virus, protein from the DNA of the virulent virus is also presented to the immune system without actual infection by the virulent virus. The advantage of a vector vaccine is that the DNA of several DNA vaccines are a variation on the vector vaccine theme. Here, a segment of viral DNA coding for an immunogenic peptide is injected directly into muscle, and synthesis of the peptide occurs in the cell. The peptide is expressed on the surface of the cell in conjunction with a type 1 major histocompatibility complex molecule and is recognized by the immune system, which is then activated and primed. DNA vaccines are still under development and none are available for human use. In order for a vaccine to be effective, it must induce the appropriate immune response. In general, both humoral and cell-mediated immune responses are made, but each has varying importance. Thus, specific antibodies inhibit enteroviruses, whereas herpesviruses are suppressed by cell-mediated immunity. The precise type of immune response that is protective is unknown for most viruses, however. Furthermore, an inactivated virus or viral subunits are often not very immunogenic by themselves, and in order to generate a sufficiently robust immune response an adjuvant must be added to the vaccine formulation. Adjuvants enhance the immune response by various means, such as attracting macrophages by inducing a mild inflammation. Some adjuvants, such as Freund's complete adjuvant, consisting of mineral oil and nonviable mycobacteria, are too toxic for human use. Currently, aluminum salts are the only adjuvants used in vaccines for human use. Safety considerations are clearly very important and include determination of adverse effects of the vaccines, such as nonspecific febrile reactions, injection site erythema and induration, and allergic reactions to the vaccine virus or its vehicle. Vaccine virus that is inadequately inactivated or attenuated can cause the disease that it is intended to prevent. Establishing the safety of vaccines before approval for human use is critical since potentially a large population can be exposed to them. Rabies is a viral encephalitis that is usually transmitted by percutaneous exposure to infected saliva from a rabid animal. The disease is characterized by dramatic and progressive neurological deficits leading to cardiovascular instability and death within a few days, following a long period after exposure. The disease has become very rare in North America since it has been eliminated from domestic animals and pets, and most cases now come from infected bats. Throughout the rest of the world, rabies poses a serious burden, with more than 50,000 deaths reported to the World Health Organization in 1983, which is almost certainly an underestimate. The idea of using modified infectious material to protect from viral disease was adopted by Pasteur, who used attenuated rabies virus from infected rabbit spinal cord to protect dogs from rabies. His strategy, which was similar to what he did to produce a chicken cholera vaccine, was to take infected rabbit spinal cord and allow it to dry, which ''weakened'' or attenuated the virus present in the cord. The longer the dessication, the weaker the virus would be until, at some point, the immune reaction induced by the attenuated virus would prevent infection by fully virulent virus. The Pasteur vaccine was first used on July 6, 1885, in a young boy, Joseph Meister, who had had multiple bites from a rabid dog. He was given 13 injections over a 10-day period and survived. The original Pasteur vaccine was thus cumbersome to administer, with multiple painful injections, and frequently gave rise to neurological complications, which were termed ''neuroparalytic accidents.'' The Fermi vaccine used live virus attenuated with phenol, and the Semple vaccine used phenol-inactivated virus. Both contained neural tissue, however, and neuroparalytic accidents remained a problem. Fuenzalida first produced a myelin-free vaccine in 1956 by propagating virus in neonatal mouse brains. The first nonneural tissuebased vaccine was the duck embryo vaccine (DEV), which consisted of vaccine virus propagated in duck eggs. This was introduced in 1956. Although the incidence of neuroparalytic accidents was greatly reduced with DEV, the vaccine was not as immunogenic as the neural tissue-derived vaccines and required 14-23 daily injections. Human cells were used to develop rabies vaccines free of animal proteins, and the human diploid cell vaccine, the contemporary standard, was first developed in the early 1960s at the Wistar Institute by growing the Pitman-Moore strain of rabies virus in the WI-38 human cell line. Currently, the vaccine is produced by growing Pitman-Moore strain in the MRC-5 human fibroblast cell line and inactivating the virus in the supernatant with b-propriolactone, after which the inactivated virus is concentrated. Rabies vaccination is usually given for postexposure prophylaxis as part of a specific regimen. The bite wound is washed with soap and water, and rabies immune globulin is infiltrated into the wound. The vaccine is then given on a defined schedule. The vaccine is very safe to use, and significant reactions are very rare. Most reactions in adults consist of soreness at the site of injection, headache, malaise, and nausea; fewer reactions occur in children. Allergic reactions to human diploid cell vaccine occur in approximately 0.1% of vaccinees but are rarely serious, and no fatalities have been reported. Polioviruses, of which there are three serotypes, are enteroviruses that usually cause a mild febrile illness in exposed children. Poliovirus was first isolated by Landsteiner and Popper in 1908. Approximately 1-5% of infections result in poliomyelitis, with patchy involvement of anterior horn cells and subsequent weakness that may be severe and permanent. The development of poliovirus vaccine is an epic tale of failed attempts, intense scientific research, and rivalry, followed by the introduction of two different successful vaccines and the eradication of the disease in the Western Hemisphere. The prospect of global eradication of poliomyelitis is not unrealistic. The first attempts at vaccination against poliovirus in the 1930s were plagued by inadequate attenuation of the virus and actually caused the disease in some of the trial subjects. Much needed to be learned. The demonstration that there were three distinct polioviruses was not achieved until 1949. There was no test for the attenuation of the viruses. There were no safety precautions against injecting neurally derived material. Scientific developments during the next 20 years led to the important realization that the virus is transmitted through fecal-oral contact and that the virus replicates in the gut before spreading to the nervous system. Further research led to the Salk vaccine, an inactivated poliovirus vaccine that was administered by intramuscular injection, and to the Sabin vaccine, an attenuated poliovirus vaccine administered orally. The trial of the Salk vaccine, begun in 1954 and completed in 1955, was done first in the United States and involved approximately 2 million subjects. The Sabin vaccine trials were done soon afterwards in the Soviet Union. Wide use of these vaccines has essentially eliminated poliomyelitis in the Western Hemisphere. The rate of poliomyelitis in the United States decreased from 10.6 per 100,000 persons in 1958 to 0.43 per 100,000 persons in 1963. Vaccination of entire populations promises to wipe the disease out worldwide. The World Health Organization has made it a priority to eradicate the disease from the earth. Measles is an acute febrile exanthem caused by the measles virus, a negative sense RNA virus. Most children with measles recover completely from the disease, but complications are not uncommon. These include bacterial superinfections, and in 1 out of 1000 cases, a postviral acute disseminated encephalomyelitis occurs that can be fatal or leave severe neurological deficits. Rarely, the virus can become established in the brain, and in 1 out of 1 million cases it leads to subacute sclerosing panencephalitis, a progressive degenerative disease of the brain, resulting almost always in death after a few months following a latent period of several years. Measles virus was first isolated and propagated in tissue culture by Enders and Peebles in 1954, and efforts at making measles vaccine followed soon thereafter. The Edmonston strain, named for the individual from whom it was first isolated, was the initial virus from which a vaccine was made. The Edmonston B strain, the actual strain used in the vaccine, was obtained from the original Edmonston isolate by serial passage in primary kidney cells (24 passages), primary human amnion cells (28 passages), chicken embryos (6 passages), and then in chicken embryo cells. This vaccine was first introduced in 1963 but was associated with a high rate of fever and rash. It was discontinued in 1975. Other vaccine strains that were much better tolerated were introduced several years before its discontinuation. One of these, the Moraten strain, introduced in 1968, was derived from the Edmonston B strain by an additional 40 passages in chicken embryo cells. The Schwarz strain was obtained from the Edmonston B strain by an additional 85 passages in chicken embryo cells and was used from 1965 to 1976. The Moraten vaccine is the only one used in the United States today. Other vaccine strains are used elsewhere throughout the world. The effectiveness of vaccination may be gauged from the fact that before vaccination 4 million cases of measles occurred annually in the United States, whereas there were only 309 cases in 1995. The difficulties in measles vaccine development are demonstrated by the formalin-inactivated measles vaccine, which was prepared from the Edmonston strain and used in the United States from 1963 to 1967. The vaccine provided only short-term protection against measles and left the recipients vulnerable to infection with measles virus. The clinical form that measles takes in these patients is atypical and severe and is marked by sudden onset of fever, headaches, dry cough, myalgias, and abdominal pain, followed by a rash beginning in the distal extremities. Most patients developed pneumonia, which resolved slowly. Patients with atypical measles had high titers of antibodies to many of the viral proteins but not to the viral fusion protein (F protein). It is thought that the formalin inactivation of the virus rendered the F protein nonimmunogenic and thus allowed cell-tocell spread, resulting in a more widespread disease. The use of this vaccine was discontinued in 1967. Mumps virus is a paramyxovirus, which causes an acute painful parotitis in children. The disease is usually self-limited, but it can be complicated by meningitis and meningoencephalitis, with residual deficits. It can also result in sensorineural deafness. In adults, mumps has a higher rate of systemic complications and can cause orchitis in up to 40% of adult men and oophoritis and mastitis in a substantial proportion of adult women. Other organs may be involved as well. The first vaccine was obtained from a young girl named Jeryl Lynn and was passaged in embryonated hen's eggs and chick embryo cell cultures. The Urabe strain was obtained from a Japanese patient. The Jeryl Lynn strain vaccine was tested in two clinical trials, one in Philadelphia nursery school and kindergarten children in 1965 -1967 and one in Forsyth County, North Carolina, schoolchildren in 1966 and 1967 Mumps vaccine was first licensed for use in 1967. The number of cases of mumps in the United States in 1968 was 152,209, and this decreased to 2982 cases in 1985. The number of cases increased briefly after vaccination rates declined but decreased again after mumps vaccination was required for school entry to 751 cases in 1996. Rubella is a self-limited febrile exanthematous disease of children caused by an enveloped RNA virus in the togavirus family. In 1940, the virus was linked by Norman Gregg to congenital cataracts in offspring of mothers who had rubella in pregnancy, and it was later realized that rubella during pregnancy could give rise to multiple birth defects. Some of these are neurological and include deafness, blindness, and microcephaly, with subsequent mental retardation and motor and language difficulties. The disease can be complicated by arthritis and in 1 out of 6000 cases by postviral acute disseminated encephalomyelitis. Rarely, the acute disease can be followed months or years later by progressive rubella panencephalitis, a progressive degenerative disease leading to death in a few months. The virus was isolated in 1962 by two different groups. Several vaccine strains were developed, but only one is currently used, the RA27/3 strain in a live virus vaccine. The virus was first isolated from the tissues of a fetus in 1965. It was serially passaged in a human diploid cell line WI-38 at two different temperatures and shown to be attenuated by inoculation into human volunteers. It was then further passaged to increase the attenuation in human diploid cell lines. The vaccine is given as a combination with measles and mumps vaccine. Vaccination against rubella has been exceedingly successful, with an incidence rate decreasing from approximately 30 cases per 100,000 persons in 1968, before the vaccine was licensed in 1969, to 128 cases total in 1995 in the United States. The incidence of congenital rubella syndrome decreased from an average of 106 cases per year in the United States in the 1970s to 20 per year currently. Varicella or chicken pox is an acute, febrile, selflimited, exanthematous disease of children that is caused by varicella-zoster virus (VZV), a member of the herpesvirus family. Complications of the disease include varicella pneumonia, hepatitis, cerebellar ataxia, and encephalitis. The disease tends to be severe in adults and the immunocompromised as well as in pregnant women, in whom the previously mentioned complications are more common. After acute infection, the virus assumes a latent state in sensory ganglia and reactivates as the host ages or when the host is immunocompromised. Reactivation results in shingles or zoster, a painful vesicular eruption located in the dermatome of the spinal nerve root in which reactivation has occurred. The pain of shingles can be quite severe and prolonged, occasionally for years after the episode of shingles, resulting in postherpetic neuralgia. Shingles is common and can affect up to 15% of the population living to the ninth decade. Shingles can affect the distribution of the trigeminal nerve and cause ophthalmic zoster, with blindness a potential complication. The reactivation of VZV in sensory ganglia can also involve the spinal cord, resulting in myelitis. Varicella virus vaccine strain was originally obtained from a 3-year-old boy, whose last name was Oka, with otherwise uncomplicated chicken pox. The virus was isolated in primary HELF cell cultures and serially passaged in multiple cell lines, and these were sonicated to release free virus. The resulting vaccine Oka strain virus was found to be temperature sensitive and to be less pathogenic in skin explants than wild-type virus. There are also differences in DNA cleavage patterns between the vaccine Oka strain and wild-type strains of virus. Clinical trials with the Oka vaccine strain began in Japan in 1974. The vaccine was first given to 70 normal children and was found to be immunogenic and protective, with no significant side effects. The safety of this attenuated vaccine strain was demonstrated in 39 children with chronic medical conditions. Subsequent studies in Japan showed that the vaccine was safe to use in children with leukemia and other malignancies if chemotherapy was stopped 1 week prior to vaccination and resumed 1 week after. Studies in the United States showed that in children with cancer and kidney transplants, the vaccine was safe, although two doses were needed to guarantee optimal protection from chicken pox. The vaccine was licensed in the United States in 1995. It is used in healthy children and adults and, with appropriate precautions, in children with leukemia and renal disease. The vaccine may help prevent shingles in the elderly by boosting anti-VZV immunity. Rare cases of shingles involving vaccine virus have been reported. Arboviruses are viruses that are transmitted by arthropods, such as mosquitoes and ticks, and are therefore not a taxonomic group but rather an ecological classification. Arboviral infections may be asymptomatic or cause a febrile rash, polyarthritis, hemorrhagic fever, or encephalitis. Examples of the latter include St. Louis encephalitis, western equine encephalitis, eastern equine encephalitis, Lacrosse encephalitis, and West Nile encephalitis in North America; Venezuelan equine encephalitis in South America; Japanese encephalitis in Southeast Asia; Murray Valley encephalitis and Kunjin fever in Australia; and tick-borne encephalitis in Europe and the Far East. Japanese encephalitis (JE) is a viral encephalitis endemic to Southeast Asia. It is caused by a flavivirus and is transmitted by mosquitoes. The disease was first described in Japan in 1871, and an epidemic in 1924 resulted in more than 6000 cases, 60% of which were fatal. Since then, outbreaks have occurred in China, Korea, Vietnam, India, and recently in Malaysia, Indonesia, Papua New Guinea, and northern Australia. The risk of disease in the unvaccinated is not negligible. In susceptible U.S., British, and Australian military personnel stationed in endemic areas, the incidence rate of JE has increased from approximately 0.05 in 1945 to 2.1 cases/week/10,000 in 1972. The virus was first isolated from human brain in 1924 by inoculation into rabbits, and the disease was transmitted into monkeys in 1934. A number of vaccines have been made since the 1930s. Currently, there are three vaccines in common use in Southeast Asia. Two are inactivated-one derived from mouse brain and the other from primary hamster kidney cells. An attenuated vaccine is obtained from primary hamster kidney cells. The Nakayama and Beijing-1 strains are used in the inactivated, mouse brain-derived vaccines, which are specially treated to remove myelin basic protein from the formulation so that the risk of postvaccine acute disseminated encephalomyelitis is minimized. A few cases of acute disseminated encephalomyelitis linked to the vaccine have been reported, but the estimated risk is very small, with less than 1 case per 1 million vaccinees. The efficacy of vaccines against JE has been demonstrated in several studies performed in Southeast Asia. The Nakayama vaccine was shown to be 80% effective in a Taiwanese study. In a Thai study, the effectiveness of both the monovalent Nakayama and the bivalent Nakayama and Beijing-1 vaccines was found to be more than 90%. The public health importance of JE vaccination is highlighted by the fact that it is included in the Thai Expanded Program of Immunizations in children, with the fourth dose of diphtheria-pertussis-tetanus and oral polio vaccine at 18 months. In Japan, there were between 1000 and 2500 cases of JE each year before vaccine was available. The number of cases decreased to near zero after 1970, soon after vaccination was instituted. In Beijing, the annual incidence rate of JE was between 15 and 30 cases per 100,000 persons per year before vaccination was available. After 1970, the incidence rate decreased to approximately 5 cases per 100,000 persons, and by 1985 the rate had further decreased to less than 1 per 100,000 persons. Tick-borne encephalitis (TBE), a disease first described in 1934, is present in central Europe and the Far East. The virus was first isolated in 1937 by Zil'ber and coworkers in the Soviet Union. Clinically, the disease may be biphasic, with an initial period of fever, malaise, headache, backache, and nausea. This is followed by an afebrile period of several days to 2 or 3 weeks, after which fever resumes, along with headache, confusion, paresis, seizures, and, in some cases, coma. Because of the tropism of the virus for anterior horn cells, surviving patients are often left with paralysis of neck and shoulder girdle muscles. Indeed, in the far eastern areas of the former Soviet Union, individuals who must prop their heads up are almost always victims of TBE. The central European form of the disease is less virulent than the far eastern form, in which mortality rates of 20-30% are reported. Older patients tend to have more severe disease. The risk of infection in susceptible U.S. military personnel living in highly endemic areas was estimated to be 0.9 cases per 1000 per month in the 1970s and early 1980s. The first vaccine against TBE was produced in 1937 using an inactivated virus prepared from infected mouse brain, and it was given to Soviet military personnel. This resulted in numerous complications. Subsequent vaccines were produced from virus grown in chicken embryo cells and inactivated with formalin. Current vaccines used in central Europe are made from virus derived from ticks and passaged serially in mouse brain and then in chicken embryos. It is then inactivated with formalin and purified by sucrose density gradient centrifugation. Although no randomized, controlled clinical trials of TBE vaccine have been done, seroconversion has been demonstrated to occur in most vaccinees with a three-dose vaccination schedule. TBE vaccine has been used in central Europe on a voluntary basis rather than being incorporated into required vaccination schedules, and approximately 35 million doses have been given in Austria since 1980, when the vaccine became available. A measure of the usefulness of the vaccine can be inferred from the decrease in incidence of the disease after the vaccine came into general use: The number of cases of TBE in Austria decreased from 677 cases in 1979 to 84 in 1992. Vaccines against eastern, western, and Venezuelan equine encephalitis are available for U.S. military personnel and veterinary and some laboratory staff but not for the general public. All three viruses are passaged in chicken embryo cells, with additional passage of eastern equine encephalitis virus in mice and guinea pigs, and inactivated in formalin. Influenza is an acute, febrile, debilitating though usually self-limited viral infection of the upper respiratory tract causing significant work and school absences each year. The elderly and chronically ill are prone to develop complications such as pneumonia, which can be lethal. Influenza can be complicated by acute disseminated encephalomyelitis and, in children, encephalopathies including Reye's syndrome. The disease occurs in yearly epidemics, in midwinter, and every few decades a completely new strain appears and causes a pandemic. Some strains are very deadly, and the 1918 influenza pandemic caused tens of millions of deaths worldwide, dwarfing mortality from the concurrent world war. Pandemics in 1957 and 1968 were serious but did not have the lethal consequences of the 1918 pandemic. The virus was first isolated in 1933 by Smith, Andrewes, and Laidlaw. In 1935, neutralizing antibodies were detected in subjects given subcutaneous injections of influenza virus. Stokes et al., who demonstrated some degree of protection, performed the first trial of an influenza vaccine in 1936. The virus was grown in a suspension of mouse lung and injected into children. Further studies of influenza vaccination were carried out by the U.S. army beginning in 1942 and 1943 and used inactivated influenza virus. The benefit of the vaccine was clear-cut. This and other studies led to the licensing of influenza vaccines in the civilian population in 1945. In 1947, there was a dramatic failure of the vaccine during an influenza epidemic, and it was found that the vaccine produced immunity to the vaccine virus but not to the epidemic strain. This was because the epidemic strain was different antigenically from the vaccine strains, illustrating the effect of the antigenic change known to occur in influenza virus. There are two types of such change: (i) antigenic drift, in which the accumulation of mutations in the genes coding for the surface antigens of the virus render it sufficiently different from the previous strains that it can cause disease despite exposure to the previous virus, and (ii) antigenic shift, in which there is reassortment of genes coding for the surface proteins. The origin of the new genetic material appears to be from strains circulating in birds. This experience led to the establishment of worldwide sentinel centers by the World Health Organization that monitor for new strains of influenza virus every year so that the new strains can be incorporated into the updated vaccine. This is an important activity since new pandemics are expected to occur in the future. Current vaccines use two strains of influenza A virus and one influenza B virus, all of which are grown in embryonated chicken eggs. Yellow fever is caused by a flavivirus transmitted by mosquitoes and can range from a subclinical infection to a mild flu-like illness and to a fulminant disease characterized by high fever, liver failure with jaundice (hence the name yellow fever), oliguric renal failure, and a hemorrhagic diathesis with hematemesis. The disease was responsible for massive epidemics in the United States in the 18th and 19th centuries. For example, an epidemic of yellow fever in Philadelphia in 1793 killed 10% of the population. The virus was first isolated in 1927 from the blood of a Ghanaian patient named Asibi (the Asibi strain). Various inactivated vaccines were developed in the 1920s but were unsuccessful. Max Theiler, working at the Rockefeller Institute in New York, developed the first successful yellow fever vaccine by serially passaging the Asibi strain in embryonated hen's eggs. This vaccine strain, the 17D strain, is an attenuated vaccine. It was first tested in 1936 and rapidly distributed. Thus, by 1939, more than 1 million Brazilians had received the vaccine. Separately, control of yellow fever in French Africa was achieved in the 1940s. The vaccine is one of the safest known, but rare cases of encephalitis in very young infants have led to the recommendation that infants younger than 4 months of age not be given the vaccine. HIV disease is caused by human immunodeficiency virus, which is an enveloped, doubly segmented, positive sense RNA virus. The virus infects CD4 þ T lymphocytes and causes their destruction during a period of approximately 10 years from the initial infection. However, T cell replenishment is gradually extinguished. The precise pathogenesis of the destruction of these cells is unknown. The result of the destruction of these cells is immunodeficiency, with the subsequent development of numerous opportunistic infections. The disease also causes a chronic inflammatory state, with weight loss, fevers, and night sweats. There are also several progressive neurological conditions linked to HIV infection, including HIV dementia, HIV myelopathy, and HIV distal sensory neuropathy. HIV disease has become pandemic, and approximately 16 million people have died from AIDS worldwide since 1980. It is estimated that 30 million people were infected with HIV worldwide by the end of 1997. This number continues to increase, especially in the Third World. Although very potent antiretroviral drugs have been introduced into the therapy of this disease, their use is limited to the more affluent societies of western Europe and North America. Given that the rate of increase of infection is highest in the Third World, the only practical way of preventing further spread of the disease is through vaccination. Despite intensive work on a vaccine, numerous difficulties have delayed the development of effective immunization. Successful vaccines have essentially abolished most childhood diseases (poliomyelitis, measles, hemophilus influenzae type B, diphtheria, whooping cough, tetanus, mumps, and rubella) that were prevalent in the U.S. population several decades ago. In order to protect a population from viral diseases, vaccines specific to those diseases endemic to that population are used. In North America, vaccines against poliomyelitis, influenza, measles, mumps, rubella, varicella, and hepatitis B are used. In Europe, additional protection may be necessary against central European tick-borne encephalitis. In Asia, protection against Japanese B encephalitis is important. Protection of special populations (the chronically ill, military personnel, laboratory workers, and travelers) mandates the use of vaccines that are not necessary for the general population. Thus, the chronically ill, who have considerable morbidity and mortality from influenza, are frequently vaccinated annually against the influenza virus strains circulating that year. Veterinarians and laboratory workers who may be exposed to rabies will be vaccinated against it. Military personnel stationed in areas of the world where certain infections are endemic need to be vaccinated against them (e.g., JE in Southeast Asia). Certain human viral diseases present attractive targets for eradication because of unique characteristics of the viruses. In order to be a candidate for VIRAL VACCINES AND ANTIVIRAL THERAPY eradication, a virus must have no reservoir in nature and not exist in a latent form in humans, from which it can be reactivated to infect naive hosts. The vaccine must produce complete, long-lasting immunity. The viral genome must be stable so that variants to which a previously infected population is susceptible do not arise. Thus, smallpox, poliomyelitis, rubella, and measles have been candidates for eradication. Smallpox has already been eradicated, and the World Health Organization has made eradication of poliomyelitis a priority. Measles, which can be devastating to children in the Third World, is also a potential candidate for eradication. Rabies has animal reservoirs and cannot be eradicated. Immunity to rhinoviruses is short-lived; therefore, the common cold will never be eradicated. Influenza virus is not genetically stable, and new variants arise yearly, so influenza epidemics occur every year and pandemics occur every few decades. The Cutter Incident: A potential problem with any vaccine containing attenuated virus is the possibility of insufficient attenuation. The most dramatic example of this occurred in the early days of Salk polio vaccination when 260 vaccinated individuals and their contacts developed poliomyelitis: 94 cases occurred in vaccinees, 126 occurred in family contacts, and 40 occurred in more casual contacts in the community. These cases could not be attributed to the patients being vaccinated just after acquiring natural infection, developing the disease before the vaccine provided effective immunity. These polio cases occurred in only a few western states, which were supplied by a single vaccine manufacturer. Another clue that these were vaccinerelated cases was the observation that the injected limbs tended to be affected with weakness. The problem was traced to lots of vaccine from one manufacturer that were inadequately attenuated. These vaccine lots were withdrawn. Vaccine from other manufacturers was found to be safe. Reversion to Neurovirulence: The Sabin attenuated vaccine is very effective in protecting against poliomyelitis. The attenuated poliovirus in the vaccine replicates in the gastrointestinal tract and stimulates mucosal immunity against the virus. The attenuated vaccine virus is excreted in the stool and may infect close contacts of the vaccinee, thus vaccinating them as well. However, because the vaccine virus is attenuated and undergoes replication in the gut, there is a possibility of reversion to a virulent form. This unfortunate possibility is rarely realized, and the Sabin vaccine has caused paralytic poliomyelitis in vaccinees or their contacts in approximately 1 case per 1 million doses. This risk is acceptable only when poliomyelitis is endemic to the population, which is no longer the case in North America. Accordingly, use of Sabin vaccine has been discontinued, and inactivated poliovirus vaccine delivered by inoculation is recommended. The original rabies vaccines were plagued by characteristic adverse events known as neuroparalytic accidents, the most severe of which was acute disseminated encephalomyelitis (ADEM), an acute inflammatory demyelination of the brain and spinal cord. Molecular mimicry is thought to be a likely mechanism, in which vaccine antigens resemble myelin antigens and immune reactions are triggered against myelin, the insulator of axons in the nervous system, with subsequent destruction of myelin and failure of conduction of impulses in the nervous system. ADEM often leads to cognitive and motor deficits in survivors. That this was due to the vaccine and not to an inadvertent contamination of the vaccine by virulent virus was deduced from the observation that most cases survived (whereas rabies is always fatal), that the pathology in those not surviving was different from that seen in rabies, and that no rabies virus could be isolated from the brains of those fatally afflicted. This complication was believed instead to be due to cross-reactivity to the myelin contained in the vaccine. As noted previously, other methods of preparation were developed to produce a myelin-free vaccine. In 1976, there were indications that a particularly virulent strain of influenza virus (swine flu) was circulating and a massive campaign to vaccinate against this strain, the National Immunization Program, was mounted in the United States. Soon thereafter, a number of cases of Guillain-Barré syndrome, an acute inflammatory polyneuropathy, were reported in vaccine recipients. Careful study of 1300 such cases led to an estimate of the risk of Guillain-Barré syndrome after swine flu vaccination to be 4.9-5.9 cases per million. Such an excess of Guillain-Barré syndrome attributable to influenza vaccine also occurred in the 1992-1993 and 1993-1994 seasons, during which a relative risk of 1.8 per 1 million for developing Guillain-Barré syndrome was found. It is not clear that the risk is specific to influenza vaccine, however. Reports of an association between measles-mumpsrubella (MMR) vaccination and the development of autism and inflammatory bowel disease have engendered much controversy. Twelve children were reported to have developed cognitive problems a few days to a few months after receiving MMR vaccination. However, the ages at which the MMR vaccine is given are also the ages when autism develops. Furthermore, there was no population-based study with controls to estimate the relative risk of autism following vaccination. A report from the Institute of Medicine concluded that there is no clear causal connection between the vaccine and autism. Certainly, autism and inflammatory bowel disease existed well before the MMR vaccine was developed, so the vaccine cannot be the sole cause of these disorders. The history of the development of antiviral drugs is not as dramatic as that of vaccines. Since the replication of viruses in mammalian cells intimately involves biochemical pathways used by the cells, interference with viral replication often results in unacceptable toxicity. Furthermore, the understanding of cellular biochemistry was a long and gradual process, so for a long time virus-specific targets were very elusive. Indeed, many of the currently used antiviral drugs had their origins in investigations of cancer chemotherapy agents, and some of the first trials of antiviral drugs used anticancer drugs. Nonretroviral viruses against which there are effective agents are shown in Table 2 . Antiviral therapies must be shown to be effective by properly designed clinical trials, which involve many subjects and therefore must be carried out by multiple closely collaborating centers. The National Each step of the viral life cycle in the cell provides a potential therapeutic target. The virus attaches to the cell, penetrates it, and replicates; viral nucleic acid and proteins are synthesized, and the nucleic acids are packaged with the proteins into virions, which are released to initiate the cycle in another cell. Some viral life cycles have unique features that are attractive antiviral targets. As a consequence, the antiviral agents tend to target closely related viruses (Tables 3 and 4) . Since DNA replication was one of the first aspects of the molecular biology of the cell to be explored, it is no surprise that antiviral strategies initially focused on this part of the viral life cycle. Thus, DNA viruses (such as herpesviruses) use cellular precursor molecules to replicate their DNA. DNA is composed of deoxynucleoside triphosphates (dNTPs) (deoxynucleoside ¼ purine or pyrimidine base þ deoxyribose), and virally programmed enzymes use cellular dNTPs to synthesize viral DNA. Acyclovir is a guanidine analog in which the deoxyribose is replaced by an acyclic structure. It was originally synthesized by Elion and Hitchings, and it was the first ''designer drug,'' specifically designed for the purpose of inhibiting DNA synthesis by viral polymerase. Acyclovir has two mechanisms of action. First, it inhibits viral DNA polymerase by competitively binding to the active site of the enzyme. Second, when acyclovir is inserted into a growing DNA chain, it terminates elongation. Acyclovir must be triply phosphorylated in order to be active. Acyclovir is first monophosphorylated by a virally encoded thymidine kinase and subsequently phosphorylated by cellular enzymes. Thus, acyclovir is active only in virally infected cells. Acyclovir is effective against herpes simplex virus-1 (HSV-1), HSV-2, and VZV infections but not against other herpesvirus infections. Ganciclovir, another guanidine analog, is notable for its effectiveness against cytomegalovirus (CMV). Acyclovir was one of the first agents shown to be effective in the treatment of herpes simplex encephalitis. Originally, studies of idoxuridine and cytarabine (a cancer chemotherapeutic agent) in herpes encephalitis showed these drugs to be ineffective, and idoxuridine was found to be very toxic. Vidarabine was investigated by the CASG in the United States, and in their 1977 publication it was shown to have efficacy, with a reduction of the mortality rate from 70% in the placebo group to 28% in the vidarabine group. Its insolubility required intravenous administration of very large volumes of fluid. From 1981 to 1985, the CASG studied the efficacy of acyclovir with that of vidarabine and found mortality rates in the acyclovir group to be 19% compared to 54% in the vidarabine group. Ribavirin is a guanosine analog that has antiviral effects against many viruses, both RNA and DNA. Its mechanism of action is not completely clear, although it is in part due to a competition with guanosine. It may also inhibit the synthesis of guanosine and deplete the pool of guanosine triphosphate available to the viral nucleic acid synthesizing apparatus. The drug is effective against influenza, parainfluenza, and respiratory syncytial viruses (RSVs) and has limited effect against adenoviruses, coxsackie A virus, rhinoviruses, and coronaviruses. It is therapeutically useful in Lassa fever and hemorrhagic fever with renal syndrome. In conjunction with a-interferon, the drug is active against hepatitis C. The drug is available in aerosol form for RSV infections in infants. A parenteral form is available for use on a compassionate basis for certain exotic viral infections, such as Lassa fever and hantavirus pulmonary syndrome. DNA replication involves the sequential addition of nucleotides to the growing DNA chain. This involves the cleavage of dNTP into deoxynucleoside monophosphate and pyrophosphate. Pyrophosphate analogs prevent this cleavage and thus inhibit viral replication. Foscarnet is a pyrophosphate analog approved for the treatment of herpesvirus infections, specifically CMV infections. The drug is effective against all herpesviruses; in addition, the replication of HIV is also inhibited. An important step in influenza virus infection is the release of viral RNA from the virus to the cell's nucleus. When the virion enters the cell, it is held in a vesicle, which acidifies in an attempt to destroy the virus. The hydrogen ions bathing the virus are directed through the viral envelope through a proton channel protein known as M2. Once inside the virion, they allow the viral RNA to dissociate from the internal scaffolding of the virus. The viral RNA is then transported to the cell nucleus. Blockers of the channel formed by the M2 protein will prevent this dissociation and thereby prevent replication of the virus. This is the mechanism of action of two drugs currently on the market, amantadine and rimantadine, used for the prevention and treatment of influenza A. Neuraminidase is an enzyme used by budding influenza virus to escape from the surface of the infected cell. Neuraminidase inhibitors prevent escape; thus, virus cannot be released from the infected cell. Viral spread to other cells is prevented and the disease duration and symptoms are improved. Neuraminidase inhibitors approved for the use of treatment of influenza A and B include zanamivir and oseltamivir. Recently, oseltamivir was shown to prevent disease in those most at risk and has received Food and Drug Administration approval for this use. In enterovirus infection, the virus attaches to susceptible cells by a slightly unusual mechanism. The virus consists of the viral RNA surrounded by an icosahedral capsid. The capsid consists of protomers, each consisting of viral proteins VP1-VP3 on the surface and VP4 below the surface. The surface of VP1 has a depression called a canyon to which the intercellular adhesion molecule-1, on a susceptible cell, binds. Once binding occurs, the virus enters the cell. The capsid then undergoes a reconfiguration and disassembles to release the viral nucleic acid. A series of compounds, known as the WIN compounds, were designed by molecular modeling to bind to the canyon floor. This inhibits binding of the virus to the cell and also prevents the release of viral RNA into the cytoplasm of the cell. One of these compounds, pleconaril, is currently being tested in clinical trials. The drug has excellent central nervous system penetration, and trials of the drug in enteroviral meningitis are under way. Unfortunately, it does not appear to be effective against enterovirus 71, the cause of severe neurological complications in some cases of hand, foot, and mouth disease in childhood. The first antiretroviral drug, a reverse transcriptase (RT) inhibitor, introduced into clinical practice was zidovudine, which was originally investigated as an anticancer drug by Jerome Horwitz in Detroit in the mid-1960s. It was unsuccessful and allowed to languish on a laboratory shelf until screening tests suggested its use as an antiretroviral drug. Initial clinical trials comparing the drug to placebo demonstrated a survival benefit in the short term, and the drug was licensed for use in AIDS in 1987. Other antiretroviral drugs followed, but the initial hope was short lived. Two main difficulties in using antiretroviral drugs became quickly apparent: the toxicity of the drugs and the fact that viral resistance to the drugs occurs readily since the virus replicates rapidly and resistance mutations arise readily because RT is an error-prone replicating enzyme. It is estimated that 10 10 virions are produced daily during HIV infection, and since there are only 10 5 nucleotide bases in the HIV genome, the rate at which mutants arise is very high. Indeed, a single HIV virion gives rise to a large number of viral variantsa ''swarm'' or ''quasispecies.'' Many of these viral variants will be resistant to whatever antiretroviral agent the patient is taking. Therefore, an initially good response to the drug will last only a few months. This prompted the strategy of combination therapy, in which several drugs with different mechanisms of action are used simultaneously so that viral replication is maximally suppressed and the opportunity for resistant viral variants is minimized. The drugs are toxic and have to be used carefully. Retroviruses reverse transcribe an RNA genome into a DNA copy, and this is an important target for therapeutic intervention since RT is not present in normal cells. This led to the idea of using nucleoside analogs that would bind specifically to RT-the nucleoside RT inhibitors (NRTIs). Zidovudine was the first such drug introduced, followed by didanosine and zalcitabine. Other NRTIs are listed in Table 4 . These nucleoside analogs bind to the active site on the RT molecule. Another class of RT inhibitors is composed of drugs that bind to RT at a site away from the active site, inhibiting its function through an allosteric mechanism. These nonnucleoside RT inhibitors are not nucleoside analogs, and they include nevirapine, delavirdine, and efavirenz. Some combinations of NRTIs have an especially potent antiretroviral effect and are incorporated into single capsules. An example is the combination of zidovudine and lamivudine, marketed as Combivir. Toxicities of zidovudine include anemia, neutropenia, and myopathy. Toxicities of didanosine and zalcitabine include a painful peripheral neuropathy and pancreatitis. The life cycle of HIV involves budding of immature virions from the infected cell. These undergo a process of maturation that is mediated by cleavage of some of the viral proteins, particularly the cleavage of gp160 into gp120 and gp41. Prevention of this cleavage renders the virion unable to infect susceptible cells. The viral protease that accomplishes this cleavage is therefore a potential target for antiviral drugs, and these form the class of protease inhibitors. These drugs were designed specifically to target HIV protease by using computer-aided molecular modeling. The first such drug to be introduced was saquinavir. Others are listed in Table 4 . A standard combination is that of ritonavir and lopinavir, marketed as Kaletra. Protease inhibitors have to be used carefully when the patient is using other medications since they have complicated interactions with liver enzymes. They also contribute to abnormalities in carbohydrate and lipid metabolism, and they may trigger diabetes and peculiar forms of lipid redistribution. New discoveries in molecular virology are occurring at a breakneck pace, opening up possible treatments on the horizon for diseases once thought to be untreatable. One exciting example concerning prion diseases such as Creutzfeldt-Jakob disease may be mentioned. Two new approaches to prion disease have recently been outlined. One consists of beta sheet breaker peptides, which bind to prion protein and disrupt the abnormal, pathogenic beta sheet configuration. Recent studies have shown that symptoms in animal models of prion disease can be considerably delayed when prions are incubated with these peptides prior to inoculation of the animal. The other approach consists of the use of cyclic tetrapyrroles, which bind to the abnormal isoform of prion protein and inhibit its pathological polymerization. Animal experiments have shown a delay in the development of prion disease when these compounds are used. See also-AIDS/HIV and Neurological Disease; Arboviruses; Enteroviruses; Influenza Virus; Rabies Virus; Rubella Virus; Varicella-Zoster Virus Further Reading Vaccines, Vaccination and the Immune Response Antiviral Therapy. Bios Scientific Neurological complications of immunization Antiviral Agents and Viral Diseases of Humans Antiviral therapy Pertussis immunization and serious acute neurological complications in children Immunization Safety Review. Measles-Mumps-Rubella Vaccine and Autism Antimicrobial Therapy and Vaccines Encyclopedia of the Neurological Sciences Copyright 2003, Elsevier Science (USA). All rights reserved. THE PERCEPTION OF COLOR involves a series of specialized neuronal processes, ranging from the photoreceptors to visual extrastriate cortex. In the 19th century, brilliant deductions were made about some fundamental aspects of color vision, such as its trichromatic nature and color opponency. However, only recently have many of the physiological, genetic, and anatomical details of this perceptual mechanism been revealed.''Color space'' is a useful concept: It refers to the fact that color has three cardinal axes. What is commonly called color is actually hue (red, green, yellow, etc.) . Saturation refers to the purity of the hue or the degree to which a pure hue is mixed with white (e.g., red vs pink). The percept of saturation and hue depend on relative differences in the activity of receptors and neurons tuned to different wavelength specificities. Brightness is the