Welcome to the 2009 edition of Epidemiology and Prevention of Vaccine Preventable Diseases. I'm William Atkinson. The Centers for Disease Control and Prevention has presented this immunization training series at least once a year since 1995. We update it annually because immunization recommendations change frequently. In the past, we recorded all 12 hours of this program every year. Beginning in 2009, our 15th anniversary, we are taking a different approach to the annual revision of the program. While there have been changes in vaccine recommendations in the past year, not everything has changed. So this year, we did new recordings of only the sections of the program that changed significantly, about 3 hours of the 12 hours of the program. We used the same facility, the CDC television studio, to record the new sections, but you might notice minor differences in the set and different presenters. We also made many other revisions throughout the program with updated graphics and voiceover inserts. For each vaccine preventable disease, we will discuss briefly the microbiology, clinical features and the epidemiology of the disease. We will not go into the diagnosis or treatment of the diseases. This information is available in many other courses and in medical textbooks. We will primarily concentrate on the vaccines and their use in your practice. The immunization recommendations we will discuss are those of the Advisory Committee on Immunization Practices or ACIP. Please note that all 2008 data are provisional and reflect reporting from the 50 states unless we indicate otherwise. Thank you for joining us for this program. We look forward to hearing from you about our new strategy for keeping it up to date. We will provide you with our contact information at the end of the session. In this segment of the program, we will discuss measles, mumps and rubella and MMR vaccine. We will briefly discuss the clinical features and epidemiology of the disease and after that we will discuss MMR vaccine and any disease specific nuances concerning the vaccine. Measles is a highly contagious viral illness that has been recognized for a long time. It was thought to be the same disease as smallpox until the 10th century and it took another 700 years before the clinical characteristics of measles were clearly described. In 1846, it was demonstrated that there was lifetime immunity following the disease. Measles is also known as rubiola. We prefer to use the term measles rather than rubiola to avoid confusion with rubella. Measles virus is a paramedicovirus with an RNA genome. It is the cousin of the virus that causes canine distemper and a disease of cattle called rindepest. It is possible that in the remote past, the ancestor of measles was an animal virus that made a species jump from dogs or cows to humans. Measles virus is rapidly inactivated by heat and light but can survive up to two hours in the air of a poorly ventilated room. Hemagglutinin is a protein in the outer coat of measles virus. It is an important surface antigen for two main reasons. First, antibodies to hemagglutinin produce immunity to measles virus. Second, subtle changes in the gene coding for hemagglutinin act like a fingerprint. As you would guess, this genetic fingerprinting is highly technical, but it allows scientists to trace back the relationship and determine the country of origin for a particular measles virus. The clinical features of measles are fairly distinct at least after the rash appears. Unfortunately, most of the transmission of measles takes place before the rash appears. After an incubation period of 10 to 12 days, there is a stepwise increase in temperature to 103 degrees Fahrenheit or higher. What usually follows is the classic triad of cough, chorizo or runny nose and conjunctivitis or pink eyes. An astute observer may see coplic spots. That's a rash found on mucous membranes a day or two before the cutaneous rash. This prodrome usually lasts two to four days. The rash appears about 14 days after exposure and is caused by deposits of measles antibody in the skin. The rash is maculopapular and appears first on the face. During the next two or three days, it descends to the trunk and then to the arms and legs. The rash fades in the order of appearance. You may have seen measles when it was common in the late 50s or early 60s or during the outbreaks more likely in the late 80s and early 1990s. For those of you who have not seen it, here's a visual aid. This is a child with measles prodrome. This prodrome usually produces a moderate illness. Notice the chorizo or runny nose and her red, teary eyes indicative of conjunctivitis. This is measles at about two days into the rash or five to six days into the illness. The rash is maculopapular and demonstrates coalescence when the discrete macules combine into larger red skin lesions. Cough is almost universal with measles. The rash is typically most intense on the head and upper chest but is usually present on the lower chest and arms. This is a dark skinned child with measles. The child has conjunctivitis and chorizo. The rash is papular or raised, not flat. A measles rash is more difficult to see with dark skin. If the rash is accompanied by other symptoms such as cough or conjunctivitis, measles is easier to diagnose. If you see or hear about a person who had an influenza-like prodrome of cough, chorizo and fever, who then developed a rash, you should suspect measles. You should be really suspicious of measles if that person is unvaccinated or has a history of recent international travel. So what should you do if you suspect measles? Well, you should obtain a blood sample for serology and a specimen for viral isolation and notify your local or state health department as soon as possible. Do not wait until the lab tests come back. Control measures must be started immediately, not a week or two later. Measles is usually a moderately severe illness but it can be very severe and have complications. The most common complications of measles are diarrhea in 8% and otitis media in about 7%. Pneumonia is reported in 6% of cases and can be either viral or bacterial. Encephalitis, which is inflammation of the brain, occurs in about 0.1% of reported cases or about 1 person per 1,000 cases. Hospitalization occurs in 18% of reported cases. Death occurs in about 0.2% of reported cases or about 2 deaths per 1,000 reported cases. As with most diseases, complication rates are not equal across ages. Most complications of pertussis, you'll recall, occur among young children and most deaths from tetanus occur among older adults. Measles complications also vary by age but there are two peaks, not just one. This graph shows by age the percentage of cases with pneumonia in the TAN bar and hospitalization shown by the green bar. Preschool age is on the left, school age in the middle and adults are shown on the right of the graph. Note there are two peaks with almost equal rates of complications, children younger than 5 and adults 20 and older. In summary, measles is an acute infectious disease with a fairly typical clinical presentation. These are fairly common and occur most often in young children and adults. The epidemiology of measles in the United States has changed dramatically and more than once in just the last few years. These changes have had a major impact on immunization programs. Measles is a human disease. Even though it may have once been an animal disease, the reservoir is now only infected persons. There are no animal or insect reservoirs and no chronic carrier state. Transmission is from person to person through the respiratory route, either by way of droplets or by true airborne transmission. Airborne transmission occurs through very small particles that remain suspended in the air. That means that direct contact with an infected person is not necessary to transmit the virus. Immersion transmission has mostly been described in closed settings such as medical exam rooms or emergency department waiting rooms. Measles peaks in the late winter. It is communicable four days before to four days after rash onset. Maximum viral shedding occurs during the prodrome before the rash appears. Measles is a very contagious disease. Very attack rates of more than 90% have been documented. This means that a person with measles will infect almost every susceptible contact. The ease of transmission of measles can also lead to explosive outbreaks, particularly in unvaccinated populations. This graph shows the number of measles cases reported by year since 1950. Before a vaccine was licensed in 1963, about 500,000 cases and up to 1,000 deaths from measles were reported every year. In reality, there were 3 to 4 million cases per year. More than 90% of the population had been infected by 15 years of age. Measles incidents fell rapidly following vaccine licensure and by 1970 reported measles cases had dropped more than 90% compared to just 10 years earlier. This graph shows the number of reported cases of measles by year since 1980. From 1980 through 1988, an average of 3,500 cases were reported per year. A major increase in measles began in late 1988. Cases increased further in 1989 and peaked in 1990 with more than 28,000 cases. This period is now referred to as the measles resurgence. This resurgence provided dramatic and unfortunate evidence of the epidemic potential of measles. More than 55,000 cases and 125 measles-related deaths were reported during the three-year period 1989 through 1991. The resurgence involved primarily unvaccinated preschool-aged children and led to large outbreaks in urban areas. It occurred because of low age-appropriate vaccination levels. The realization that vaccine coverage was poor led directly to the Childhood Immunization Initiative of the 1990s, which gave us new immunization strategies, such as AFIX. These strategies are discussed in the course text. This graph shows the age distribution of reported measles cases from 1975 through 2005. The vertical axis shows the percent of reported cases in three age groups. School-aged children are in pink, preschool children in blue, and adults in green. During the 1970s and most of the 1980s, at the left of the graphic, school-aged children accounted for the majority of measles cases. In some years, up to 80% of cases were reported in this age group alone. During the measles resurgence in the early 1990s, preschool-aged children in the blue line comprised the largest age group. Since 1995, there has been no predominant age group for measles cases. All three groups account for about a third of the small number of cases, but the biggest proportionate increase has been in the percent of cases contributed by adults, shown by the green line. During the 1970s, adults accounted for less than 10% of cases. Now adults account for a third to half of all reported cases. Many of these cases in adults are international travelers and health care personnel who are inadequately vaccinated. During the measles resurgence of 1989 through 1991, large outbreaks of measles occurred among unvaccinated preschool-aged children. In response to the outbreaks, major immunization efforts were undertaken across the country. As a result of these efforts, measles immunization levels went up and the outbreaks stopped. Measles vaccination levels among two-year-old children went from about 60% in the late 1980s to higher than 90% now. The result of these high immunization levels is record low numbers of measles cases. From 2000 through 2006, an average of only 66 cases were reported per year. A record low annual total of only 37 cases was reported in 2004. Indigenous transmission of measles virus has been interrupted in the United States. Many of the cases are among older children and adults who are either unvaccinated or have received only one dose of vaccine. Many measles cases are imported, meaning the infection was acquired while traveling outside the United States. Many of the remaining cases are linked to importation. For example, in 2006, 52 of 55 reported cases or 95% were imported or traceable to importation. In 2008, a provisional total of 132 measles cases was reported, the largest annual total since 1997. 89% of these cases were imported from or associated with importations from other countries, particularly countries in Europe where several outbreaks are ongoing. 76% of cases were among persons younger than 20 years of age. 91% were in persons who were unvaccinated, most because of personal or religious beliefs or of unknown vaccination status. The increase in the number of cases of measles was not a result of a greater number of imported measles cases. It was the result of more measles transmission after the virus was imported. The importation associated cases occurred largely among school-aged children who were eligible for vaccination but whose parents chose not to have them vaccinated. Many of these children were homeschooled and not subject to school entry vaccination requirements. Our experience in 2008 again demonstrates the threat of measles outbreaks in groups or areas with low vaccination levels. More information about measles in 2008 is available on the Program Resources webpage. For a few persons with measles, the source of the virus is not known. It is a high priority for us to determine the source of the virus for all persons with measles reported in the United States. The measles laboratory at CDC has the technical capability to determine the geographic origin of viruses, but they need your help to obtain the specimens. Specimens for viral isolation should be obtained from every person with suspected measles that you see. CDC has published detailed instructions on the collection of specimens for virus isolation. We will include a link to these instructions on the Updates and Resources webpage. In 1999, the World Health Organization set a goal to reduce by 50% the number of deaths due to measles throughout the world by 2005. That year, WHO estimates that more than 800,000 measles-related deaths occurred, mostly among children younger than five years. WHO estimates that because of increased efforts to improve measles vaccination in developing countries, the number of deaths in 2005 was reduced by 60% to about 345,000 deaths. The largest total reduction was in Africa. WHO estimates that improved measles immunization prevented two to three million deaths from measles between 1999 and 2005. This is an historic victory for global health. Continued efforts to implement measles vaccine programs in developing countries should prevent even more sickness and death. We look forward to the day when measles is no longer a threat to any child anywhere. Andrew? Mumps is an acute viral illness. Both perititis and orchitis were described by Hippocrates in the 5th century BC. By 1934, it had been deduced that a virus caused the disease, although the virus was not isolated until 1945. Mumps was a frequent cause of outbreaks among military personnel in the pre-vaccine era. During World War I, only influenza and gonorrhea were more common causes of hospitalization among soldiers. Outbreaks of mumps have been reported among military personnel as recently as 1986. The incubation period of mumps is 14 to 18 days. It may have a nonspecific prodrome of fever, headache, malaise, and myalgias. The clinical finding most commonly associated with mumps virus infection is perititis, but occurs in only 30 to 40 percent of infected persons. Up to 20 percent of infections are asymptomatic. 40 to 50 percent have nonspecific or respiratory symptoms. Mumps may present as lower respiratory illness, particularly in children younger than five years of age. Here's a child with perititis. Perititis may be unilateral, like in this child, or bilateral. A person who recovers from unilateral mumps perititis will be immune and will not be susceptible to developing mumps again later on the other side. Mumps is generally a mild illness and classic perititis seems to be the exception rather than the rule, but complications may occur and they may occur without evidence of perititis. Central nervous system involvement is reported in about 15 percent. CNS involvement is more frequent among adults than children and generally presents as aseptic meningitis. In fact, in the pre-vaccine era, mumps virus was one of the most common causes of aseptic or viral meningitis. There may be permanent sequelae such as paralysis, seizures, and cranial nerve palsies. Orchitis or involvement of the testicle in post-puberty males occurs in 20 to 50 percent of cases in this age group. Testicular atrophy may result, but mumps is a rare cause of male infertility. Ophritis, inflammation of the ovary, also has been reported. Deathness occurs once in 20,000 cases and is usually permanent. Death is uncommon, one to three per 10,000 reported cases. Mumps is a human disease. The reservoir is persons with the acute illness. There is no carrier state or animal or insect vector. It is transmitted by respiratory droplets and subclinical infections may transmit the virus to susceptible contacts. Mumps is communicable three days before to four days after onset. Mumps seems to be less communicable than measles with secondary attack rates documented at about 30 percent. Measles has secondary attack rates in excess of 90 percent. This graph shows the number of mumps cases reported by year since 1968 when it first became reportable. Live attenuated vaccine had been licensed a year earlier. In 1968, 152,000 cases and 25 deaths were reported, which is a rate of 88 cases per 100,000 population. Incidents fell during the next 10 years, falling below 10,000 cases for the first time in 1980. This graph shows the number of mumps cases reported by year since 1980. Two to five thousand cases per year were reported throughout most of the 1980s. The spike in the middle of the graph represents outbreaks in 1987 and 1988 that mostly involved school children. Some of these children had been previously vaccinated, illustrating the potential for transmission among persons with vaccine failure. But the majority of outbreaks occurred in states in which mumps was not included in school entry requirements. A large multi-state outbreak of mumps occurred in the United States in 2006. The first cases in the outbreak were detected on a college campus in eastern Iowa in late 2005. The outbreak primarily involved seven Midwest states, although an increase in cases was reported by almost every state in the country. The source of the initial cases is unknown, but the mumps genotype G virus that was isolated from persons in many states during the outbreak was genetically identical to one known to circulate in the United Kingdom. The median age of persons reported with mumps was 22 years. The highest incidence was among young adults 18 through 24 years of age, many of whom were college students. However, the outbreak spread to all age groups. Transmission of mumps virus occurred in many settings, including college dormitories and healthcare facilities. The largest number of cases was reported from Iowa. Among approximately 1800 persons with completed follow-up reports in Iowa, about half had received two or more doses of MMR and 14 percent had received one dose. Multiple factors might have contributed to the spread of mumps in this outbreak. First, crowding and close contact in the college campus environment facilitates transmission of mumps and other illnesses that are spread through respiratory and oral secretions. Second, lack of a two-dose MMR college entry requirement or lack of enforcement of a requirement probably contributed. Only three of the seven most affected states had a college admission requirement of two doses of MMR vaccine and these requirements may not have been rigorously enforced. Delayed recognition and diagnosis of mumps might have contributed to the spread in this outbreak. Younger physicians in the United States likely have not seen mumps and physicians might not consider the diagnosis, especially in vaccinated persons. Mumps vaccine failure may have had a role. Two doses of mumps vaccine are not 100 effective in preventing disease. Accumulation of susceptible persons who are not successfully immunized might be sufficient to sustain transmission in certain settings. This fact notwithstanding, two doses of mumps vaccine likely prevented mumps infection in nine out of every ten persons exposed. Even in highly affected college campuses, attack rates were much lower two to four percent than during mumps outbreaks 20 years ago when attack rates were commonly six to 18 percent in settings with high one-dose vaccine coverage. In addition, the vaccine might be less effective in preventing asymptomatic infection or atypical mumps than in preventing paratitis and persons with asymptomatic infection or mild disease might contribute to transmission. Finally, waning immunity has been postulated as a contributing factor in this outbreak. Young adults 18 through 24 years of age would most commonly have received their most recent dose of mumps containing vaccine as long as 17 years ago. The number of cases of mumps declined in the second half of 2006 and in 2007. But healthcare providers should remain alert for suspected mumps cases, conduct appropriate diagnostic testing and report these cases to local or state health departments. As a result of this outbreak, the ACIP revised several of its recommendations for mumps vaccination. We will discuss these changes later when we discuss MMR vaccine. Bill? Rubella was first described as a distinct clinical entity in in the German literature in the 18th century, hence the common name German measles. Prior to that time, most physicians thought it was a variant of measles or a combination of measles and scarlet fever. It was not until 1941 that Norman Gregg, an Australian ophthalmologist, recognized the connection between maternal rubella infection and congenital cataracts and heart defects and described congenital rubella syndrome. Rubella virus was first isolated in 1962. About the same time, a pandemic of rubella occurred in Europe and America. Thousands of families suffered because of the miscarriages and birth defects caused by rubella virus. This helped stimulate the development of a vaccine. Rubella is a toga virus with an RNA genome. Other toga viruses include Eastern, Western and Venezuela and equine encephalitis viruses and the Ross River virus, all of which are transmitted by mosquitoes. There is no evidence that rubella virus is transmitted by mosquitoes. There is only one antigenic type of rubella virus. The virus is rapidly inactivated by heat and light so it does not persist long in the environment. The incubation period of rubella is 12 to 23 days but averages 14 to 16 days. There may be a prodrome consisting of low-grade fever and malaise. Lymphadenopathy or enlarged lymph nodes may appear in the second week. The rash appears 14 to 17 days after exposure. Rubella is generally a mild illness. In fact, up to half of infections are inapparent or subclinical. Here's a short video that shows a child with a moderate case of rubella. This child has rubella. The rubella rash usually begins and is most noticeable on the face but may involve other parts of the body. The rash usually lasts about three days hence its common name of three-day measles. These are the enlarged post-irricular lymph nodes seen frequently with rubella. Posterior cervical and suboccipital nodes may also be involved. Notice that the rash is much more sparse on the trunk and arms than on the face. The rash is typically fainter than a measles rash and does not coalesce. The rash is more prominent after a hot shower or bath. There are a few complications of rubella that you should be aware of since similar but milder symptoms occur as adverse reactions following vaccination. The most common are arthralgia or joint pain and arthritis or inflammation of a joint. Joint symptoms are rare in children but joint symptoms are reported in up to 30% of adults and in 50 to 70% of adult females with rubella. Chronic and recurrent joint symptoms have also been described following rubella in adult women. Thrombosidopenic perpura occurs once in 3,000 cases and encephalitis is reported once in 5,000 to 6,000 cases. The real public health significance of rubella is not the disease itself nor its complications. It is congenital infection. The virus may infect many different embryonic cell lines and may cause damage to many different organs. Collectively, these abnormalities are known as congenital rubella syndrome or CRS. Unfortunately, the mother does not have to be symptomatic to transmit the virus to her fetus. Inapparent infections in the mother may lead to CRS. In general, the younger the fetus when infected, the more serious the damage. Up to 90% of infants born to women infected with rubella virus in the first 11 weeks of pregnancy will have defects. Infection early in pregnancy may also lead to fetal death and miscarriage. Fortunately, CRS is rare with second trimester infection. Here's a list of some of the most common anomalies associated with CRS. The most common defects are the classic triad of deafness, cataracts, and heart defects. Microcephaly or small head is also common. Mental retardation is common and may not become apparent until the child is a few years old. Now these are just a few of the common abnormalities. Defects have been described in virtually every organ. This child has congenital cataracts, one of the most common findings in congenital rubella syndrome. Infants born with CRS may have other eye defects such as glaucoma and retinal abnormalities. Many children with congenital rubella syndrome are permanently disabled. The good news is that virtually every case of CRS could be prevented with a single dose of rubella vaccine. Rubella is a human disease and the reservoir is acutely infected persons. There is no animal or insect vector of rubella virus. Transmission of rubella is respiratory. It's communicable seven days before to five to seven days after rash onset. But subclinical or asymptomatic cases may also transmit the virus. Infants infected in utero with rubella virus may shed virus for a year or more. This graph shows the number of rubella cases reported by year since 1966 when the disease became nationally reportable. That year there were 47,000 cases and 12 deaths. Rubella peaked in 1969 with 58,000 cases and 29 rubella deaths. Following licensure of the first rubella vaccines cases fell rapidly to 12,000 in 1979. This graph shows reported rubella cases by year since 1980. Since 1983, fewer than 1,000 cases of rubella have been reported annually except in 1990 with 1100 cases and 1991 with 1,400 cases. These increases were due to large outbreaks in California in 1990 and among the Amish mostly in Pennsylvania in 1991. This next graphic overlays the number of reported cases of congenital rubella syndrome shown in the blue line. Notice the similarity in the shapes of the rubella and CRS lines. CRS fell along with rubella in the early 1980s. The little peak of CRS in 1986 was a cluster of cases in New York City that was not associated with an increase in reported rubella cases. The big peak in CRS follows the rubella outbreak in California in 1991 and following the outbreak among the Amish in Pennsylvania in 1992. Until recently, most countries of the world including most in Latin America did not use rubella vaccine. So, immigrants from these areas are more likely to be susceptible to rubella than U.S. natives. The good news is that as of 2006, 43 of the 44 countries in the Western Hemisphere, all except Haiti, have introduced rubella-containing vaccine into their national programs. We understand that Haiti plans to include rubella vaccine in their national program in the near future. But many foreign-born adults remain susceptible to rubella. Vaccination programs targeting immigrants from these areas, particularly programs in workplaces, could help reduce susceptibility and prevent rubella and CRS in these persons. An all-time low of 7 cases of rubella were reported in 2003. 11 cases were reported in 2005 and 2006. 10 infants with CRS had been reported since 2001. In October 2004, the CDC convened an independent expert panel to review available rubella and CRS data. After a careful review, the panel unanimously agreed that rubella was no longer endemic in the United States, making it the fourth viral infection to be eliminated from the United States by vaccination. Donna? The first measles vaccine became available in 1963. The vaccine currently used in the United States was licensed in 1968. An inactivated mumps vaccine was available in the United States from 1950 until 1978, but provided limited protection. The current live attenuated mumps virus, the Gerald Lynn strain, was licensed in 1967. The first rubella vaccines were licensed in 1969. The current strain, called RA-273, replaced the earlier strains in 1979. Combined measles mumps rubella vaccine was licensed in 1971. The most recent development was the licensure in 2005 of a combined measles mumps rubella varicella vaccine, or MMRV. The measles mumps and rubella components of MMRV are identical to MMR. MMRV has seven to eight times as much varicella vaccine virus as does monovalent varicella vaccine. MMRV is approved only for children 12 months through 12 years of age and should not be administered to anyone 13 years of age or older. MMR vaccine is a live virus vaccine. The efficacy of a single dose has been estimated at 80 to 95 percent, depending on the component. Single dose mumps vaccine efficacy is estimated to be 80 to 90 percent. Single dose measles and rubella vaccine efficacy are 90 to 95 percent. Duration of immunity appears to be very long, probably lifelong. Even though single dose efficacy is high, the routine MMR schedule is two doses. ACIP and the American Academies of Pediatrics and Family Physicians recommend that MMR or MMRV be used whenever one or more of its components are indicated. In fact, single antigen component vaccines are not available. Merck no longer produces single antigen measles mumps and rubella vaccines for distribution. 12 months is both the recommended age and the minimum age for any measles mumps rubella or varicella containing vaccine, either single antigen MMR or MMRV. This is because it is the earliest age at which almost all children have lost their maternal antibodies, which can interfere with vaccine virus replication. A dose given before 12 months of age should not be counted as a valid dose. The child should be re-vaccinated on or after the first birthday. Doses given up to four days before the first birthday may be counted if your state accepts the grace period, as discussed in the general recommendations on immunization. Although MMR vaccine is highly effective, not everyone responds to the first dose. Numerous studies conducted during the last 20 years have shown that some recipients do not respond to the first dose, even given at the appropriate age. The vaccine failure rate varies by component. 5% for measles and rubella and up to 20% for the mumps component. The reason why this small number of persons do not respond to the vaccine is not known with certainty, but it is probably caused by antibody present at the time of vaccination or mishandled vaccine that was damaged or recording errors or possibly other causes. The good news is that vaccine failure is not permanent and most persons with vaccine failure of the first dose will respond to a second dose. More than 99% of persons with two doses of MMR after the first birthday will be immune to measles and rubella and 90% immune to mumps. This is important because these diseases, particularly measles, are highly contagious to prevent outbreaks. Nearly 100% of the population must be immune. Achieving this high population immunity requires two doses of vaccine, not just one. The second dose of MMR vaccine is intended to produce immunity in persons who fail to respond to the first dose. The second dose is not really a booster dose. It is possible that the second dose may increase antibody titers in some persons, but this increased antibody titer typically does not persist very long. The first dose of MMR or MMRV is recommended at 12 to 15 months of age. The second dose of MMR or MMRV should be routinely administered at 4 to 6 years of age at entry to kindergarten or first grade. However, the second dose may be given earlier than 4 to 6 years of age. This issue has become more complicated with the second dose varicella vaccine recommendation and the availability of MMRV. Two doses of MMR can be separated by four weeks. However, two doses of varicella vaccine must be separated by at least three months for children younger than 13 years of age. So if the first dose of varicella vaccine is given at the same visit as the first MMR or if MMRV is used for the first dose and you want to use MMRV for the second dose, then it must be given at least three months after the first dose. This is not as convoluted as it seems at first. Just remember that two doses of varicella vaccine alone or in combination with MMR must always be separated by three months for children younger than 13 years of age. All children of school age and older should have two documented doses of MMR vaccine. The routine health assessment at 11 or 12 years of age should be used as a checkpoint to make sure that no child enters adolescence without having received two doses. Andrew. Since 1977 when MMRV vaccine was first recommended for routine vaccination of children, appropriate vaccination has been defined as one dose of MMRV containing vaccine on or after the first birthday. A second routine dose of measles vaccine preferably administered as MMR was recommended in 1989. As a result of this recommendation many persons have received two doses of MMR but many older persons have not received a second dose. The 1998 MMR ACIP statement reiterated that mumps immunity was defined as one dose on or after the first birthday. The 2006 mumps outbreak underscored limitations in the 1998 recommendations relating to prevention of mumps transmission in healthcare and other settings with high risk for mumps transmission. After reviewing data from the outbreak and previous evidence on mumps vaccine effectiveness and transmission the ACIP issued updated recommendations for mumps immunity and vaccination in June 2006. Acceptable presumptive evidence of measles and mumps immunity now includes one of the following documentation of adequate vaccination, laboratory evidence of immunity, birth before 1957 or documentation of physician diagnosed measles or mumps. Evidence of measles and mumps immunity through documentation of adequate vaccination is now defined as one dose of MMR vaccine for preschool aged children and adults not at high risk of exposure to measles and mumps. Two doses of MMR are now recommended for school aged children, grades kindergarten through 12th grade and for adults at high risk of exposure. Adults at increased risk of exposure include college students, international travelers, and healthcare personnel. College students who live in dormitories are at particularly high risk. International travelers are at increased risk if they visit areas where measles is more common than it is in the U.S., which is almost everywhere in the world. College students and international travelers younger than 50 years of age should receive two doses of MMR vaccine if they do not have other evidence of measles immunity. Healthcare personnel are at particularly high risk of measles because they can unknowingly be exposed to measles at almost any time. Nozocomial measles transmission has been documented in the offices of private physicians in emergency departments and on hospital inpatient units. The risk of measles infection in healthcare personnel is estimated to be 13 times higher than for the general population, so measles immunity in healthcare personnel is especially important. In 1997, ACIP and the Hospital Infection Control Practices Advisory Committee published comprehensive recommendations for the immunization of healthcare personnel. This document is a bit dated now but the recommendations for measles immunity are still valid. The ACIP recommends that all persons who work in medical facilities should be immune to measles, not just those beginning employment and not just those with direct patient care responsibilities. This recommendation includes students and volunteers as well as medical and non-medical employees. Persons who were born in or after 1957 and work in medical facilities should have serologic evidence of immunity, documented physician diagnosed measles meaning a written dated record or documentation of two doses of measles vaccine. Because of the importance of measles immunity in healthcare personnel ACIP recommends that facilities implement policies that require a dose of measles vaccine for persons born before 1957 unless they have other evidence of measles immunity. Mumps transmission in medical facilities has been documented in the past and was also documented during the 2006 outbreak. Exposure to mumps in healthcare settings can result in added economic costs associated with furlough and reassignment of staff members from patient care duties or closure of wards. All persons who work in medical facilities should be immune to mumps. Healthcare personnel born in 1957 or later without other evidence of immunity should have documentation of two doses of a mumps containing vaccine. The minimum interval between doses is 28 days. Healthcare personnel who have received only one dose previously should receive a second dose. Because birth before 1957 is only presumptive evidence of immunity medical facilities should consider recommending one dose of a mumps containing vaccine for unvaccinated workers born before 1957 who do not have a history of physician diagnosed mumps or laboratory evidence of mumps immunity. During a mumps outbreak medical facilities should strongly consider recommending two doses of mumps vaccine to unvaccinated personnel born before 1957 who do not have evidence of mumps immunity. These new recommendations for healthcare personnel are intended to offer increased protection during a recognized outbreak of mumps. However, reviewing healthcare personnel immune status for mumps and providing vaccine during an outbreak might be impractical or inefficient. So staff should consider reviewing the immune status of healthcare personnel routinely and providing appropriate vaccinations including mumps vaccine in conjunction with routine annual disease prevention measures such as influenza vaccination or tuberculin testing. You might have wondered what is so special about 1957. It is generally assumed that persons born before 1957 are immune to measles because they had the disease as a child but the 1957 cutoff for measles and mumps immunity is somewhat arbitrary. Serial prevalence studies in healthcare personnel show that up to five percent of persons born before 1957 are susceptible to measles and mumps. Five percent susceptible is probably okay for adults at low risk of exposure but it is not okay if you are at high risk of exposure and healthcare personnel are among the most likely to be exposed to a person with measles and mumps. After all, where else would someone go who has a cough, a rash and a temperature of 104? Bill? The definition of rubella immunity is different than those for measles and mumps. A person can be considered immune to rubella if they have documentation of one dose of rubella containing vaccine, serologic evidence of immunity or were born before 1957. Unlike measles and mumps, a personal or physician diagnosed history of rubella disease is not considered reliable and is not acceptable as evidence of rubella immunity. Birth before 1957 does not guarantee rubella immunity just like it does not guarantee immunity to measles or mumps. Because of the potential for congenital rubella syndrome, if a woman is infected during pregnancy, ACIP recommends that birth before 1957 not be accepted as evidence of rubella immunity for women who might become pregnant. For women of childbearing age, ACIP recommends that only serology or documentation of at least one dose of rubella vaccine should be accepted as evidence of rubella immunity. Using a strict definition of rubella immunity adds another layer of safety to our congenital rubella syndrome prevention efforts. CRS is a disease we would prefer to never see again. Now a couple of comments on serologic testing. Occasionally you will encounter a person with a documented history of one dose of rubella vaccine who has a negative rubella screening serology. We suggest you just go ahead and give the person a second dose of MMR although the problem is most likely an insensitive test rather than true susceptibility. Once a person has been tested and found to be immune, no further testing needs to be done. There is no evidence that immunity to rubella wanes with time since vaccination. The ACIP recommends no more than two total doses of MMR for anyone. So if a person is found to have a negative serology after two documented doses of MMR, additional vaccine is not recommended. Donna. Since MMR vaccine contains live viruses it has more contraindications and precautions to vaccination than inactivated vaccines. These contraindications and precautions apply to the model valent component vaccines MMR and to MMRV with one exception that I'll point out in a moment. A severe allergic reaction to a vaccine component or following a prior dose of vaccine is a contraindication as it is for all vaccines. In the past egg protein was believed to be responsible for the rare anaphylactic reaction following MMR vaccines. Evidence now suggests that gelatin which is used as a stabilizer in MMR and MMRV may be responsible. Measles and mumps vaccine viruses are grown in chick embryo fiber blast tissue culture and do not contain ovalbumin. Several studies have demonstrated the safety of MMR in egg allergic children. As a result the ACIP and AAP recommend that you vaccinate even egg allergic children without prior skin testing or the use of protocols requiring gradually increasing doses of vaccine. Pregnancy is a contraindication to measles and MMR vaccines because of the theoretical risk of damage to a developing fetus. MMRV is not approved for persons 13 and older so pregnancy should rarely be an issue. Neither measles vaccine nor MMR has ever been shown to injure a fetus. Although the manufacturer recommends a three-month delay ACIP recommends that pregnancy should be delayed for four weeks after a dose of MMR. MMR vaccine viruses are not transmittable so pregnancy of a household contact is not a contraindication to vaccination of a child or other household member. The pregnancy contraindication can be problematic for providers who see women of childbearing age so let's review the recommended procedure for screening and vaccination of such women. ACIP recommends that you ask if the woman is pregnant or likely to become pregnant in the next four weeks. It is a good idea to ask what form of contraception is being used. This is because women who are sexually active and not using contraception still might tell you they could not become pregnant in the next month. Exclude women who are or may become pregnant in the next four weeks. For those women who are not excluded by these questions explain the theoretical risk of vaccination during pregnancy and the importance of not becoming pregnant during the four weeks following vaccination. Then vaccinate them. ACIP does not recommend routine pregnancy testing of women before rubella vaccination. Inadvertent vaccination of women who are pregnant is bound to occur even with careful screening. Several studies have examined the risk of CRS following vaccination including an American study conducted from 1971 through 1989. It was called the Vaccine in Pregnancy or VIP study. 321 women were enrolled after they were inadvertently vaccinated near or after conception. There were 324 live births including three sets of twins. There were no cases of CRS observed among these births. Now if you calculate the 95 percent confidence limits you find that the risk of CRS in this situation is between 0 to 1.2 percent. That is what we are referring to when we say there is a theoretical risk. In reality no case of CRS following rubella vaccination in pregnancy has ever been documented. None of us intend to vaccinate a pregnant woman but what if despite your diligent screening you do you should reassure her that no case of congenital rubella syndrome has ever been reported in a woman vaccinated during pregnancy. You should also let her know in terms she will understand that the ACIP does not consider rubella vaccination alone sufficient reason to terminate a pregnancy. Of course the final decision about management of the pregnancy lies with the woman and her physician. Immunosuppression which we use synonymously with immunodeficiency and immunocompromised is also a contraindication to measles vaccine. MMR vaccine should not be given to persons taking large daily doses of oral or parenteral corticosteroids for more than two weeks. It should not be given to persons with cancer or those being treated for cancer. Measles containing vaccines should be delayed for at least one month after high dose steroids or immune modulators such as etanercept and at least three months after chemotherapy. MMR vaccine virus infections are non-communicable in usual circumstances. There is no risk of transmission to a household contact. As a result MMR is recommended for the healthy household contact of an immunosuppressed person. A related issue is the use of measles containing vaccine in persons with HIV infection. Measles can be lethal to a person with HIV infection so MMR continues to be recommended for persons with asymptomatic HIV infection. MMR is not recommended for persons with evidence of severe immunosuppression from HIV. Severe immunosuppression is defined by low CD4T lymphocyte counts or the percentage of total lymphocytes. There's more information about the lymphocyte count criteria for severe immunosuppression in the 1998 MMR ACIP statement. Pre-vaccination HIV testing of an otherwise healthy person is not recommended. There are no data on the efficacy or safety of MMRV in persons with HIV infection. Consequently MMRV is not recommended or approved for persons with HIV infection regardless of symptoms or degree of immunosuppression. There are two precautions for both MMR and MMRV. Moderate or severe acute illness is a precaution and vaccination should be delayed until the acute illness improves. This precaution applies to all vaccines. Recent receipt of a blood product is a precaution because of potential inactivation of the vaccine virus. Passive antibody from blood products may affect all three viruses in MMR and varicella if you are using MMRV. The vaccine and antibody table and the general recommendation should be your guide for timing of blood products and either measles or varicella-containing vaccine. Andrew? Since all three components of MMR are live viruses, adverse reactions following vaccination are predictable. They represent viral replication that leads to mild illness in susceptible vaccine recipients. Adverse reactions following live vaccines generally occur after an incubation period of the vaccine virus. For MMR vaccine, this is seven to ten days after vaccination. The most common adverse reaction following MMR vaccine is a low-grade fever. This occurs in about 5 to 15 percent of recipients. Fever is usually attributed to the measles component but may be caused by any of the three vaccine viruses. Febrile seizures may follow. Antipyretics like acetaminophen or ibuprofen may prevent fever and febrile seizures but the onset of fever following live vaccines is often sudden and unpredictable so it is difficult to use antipyretics for this purpose. A rash occurs in about 5 percent of recipients and lasts a day or two. The rash is also usually attributed to the measles vaccine component but may also be caused by rubella vaccine virus. The rash is much milder than the rash that occurs with measles disease. Joint symptoms occur in up to 25 percent of rubella susceptible women, less in men and rarely in children. The most common joint symptoms reported after rubella or MMR vaccination are arthralgia or joint pain and arthritis or joint swelling and redness. Remember that joint symptoms are more common after rubella disease occurring in up to 70 percent of adult women. The onset of joint symptoms is usually one to three weeks after vaccination or an incubation period of the vaccine virus. Symptoms last from one day to about three weeks and rarely recur. These symptoms are usually not severe enough to cause absence from work. There have been reports from some investigators of persistent pain or chronic arthritis in women who received rubella vaccine. However, several large epidemiologic studies have not found an association between chronic joint symptoms and rubella vaccination. Many adult women are receiving a second dose of MMR vaccine for employment or college entrance and are concerned about joint symptoms after this dose. There appears to be very little risk. Almost everyone becomes immune to rubella after the first dose. Immune women do not have joint symptoms after vaccination so the chance of joint symptoms after a second dose are quite small. The only women who would be at risk for joint symptoms are the small number who failed to respond to the first dose. Thrombocytopenia or low platelet count is clinically apparent after less than one in 30,000 doses. It is usually transient and benign. On rare occasion, bleeding does occur. Perotitis and deafness are rare, adverse reactions, usually attributed to the mumps component. Encephalopathy is believed to occur after one in a million doses or less. This is a very rare event, again much less frequent than encephalopathy following measles disease. The adverse reaction profile of MMRV is similar to that of MMR. In trials that compared adverse reactions following MMRV to those following MMR and varicella vaccines administered separately, only fever occurred more commonly in the MMRV group. Fever of 102 degrees or higher within 42 days was reported in 22 percent of MMRV recipients compared to 15 percent of those who received separate injections. This increased occurrence of fever may be the result of the higher titer of varicella vaccine in MMRV. Many parents are concerned about an association between measles vaccine or MMR and autism. This concern is amplified by sensational and unbalanced media. Multiple large, well-designed studies have provided evidence that there is no association between MMR and autism. A 2009 court decision agrees with the science. On February 12, 2009, the U.S. court of federal claims as part of the omnibus autism proceedings ruled that there is no medical or scientific basis for an association between autism and vaccines. Hopefully this ruling will help reassure parents that vaccines do not cause autism. More information on this issue is available on the CDC vaccines and immunization website. One other issue I would like to mention is measles vaccine and tuberculin skin testing. It has been known for years that measles disease could cause a person with a latent tuberculosis infection to develop active TB. But measles vaccine does not exacerbate TB, so testing is not a prerequisite for vaccination. In the 1960s, it was observed that the early measles vaccine, the Edmondson vaccine, could suppress the response to a tuberculin skin test or TST. Cell-mediated immunity is suppressed by viral infections, including measles and measles vaccine. Cell-mediated immunity to TB antigens is what you are measuring with a TST. If you give measles vaccine first, then place a TST during the period of immune suppression. The response to the skin test may be reduced, even if the person does have a TB infection. It is not known if the current more attenuated vaccine also has this effect, but it's safer to assume it does and not risk interference with the accurate reading of a TST. To minimize the risk of interference between measles vaccine and TST, the preferred strategy is to apply the TST at the same visit during which measles-containing vaccine is administered. The mild immunosuppressive effect of the vaccine will not be a problem for a few days. This strategy is preferred because it avoids missing the opportunity for MMR vaccination. A second strategy is to apply the TST first and administer the vaccine when the person comes back to have the test read. This strategy is least preferred because if the person does not come back for the TST reading, you have missed the opportunity to give the vaccine. What you should not do is apply a TST if a measles-containing vaccine has already been given. You should delay the TST for at least four weeks if the vaccine is administered first. By delaying the TST, if the MMR or MMRV has already been administered, you will eliminate the risk of vaccine suppression that could lead to a false negative skin test. A false negative TST could delay treatment of a person with tuberculosis. We suggest you apply these TST rules to all injected and intranasal live vaccines just to be safe. We would like to present a case study now that addresses issues we've discussed on the program today. The case studies are available on the updates and resources webpage for this program. Here's today's first case study. Raysa is a three-year-old adopted from Russia. It's her first visit to your office in November. She is known to be HIV positive and her T lymphocyte percentage is 12 percent with a normal range of 32 to 68 percent. She otherwise appears healthy. There's no record or knowledge of her having had chicken pox. Her translated vaccination record indicates that she has had BCG vaccine at birth, aurel polio vaccine at birth, one month, three months, and four months of age. The record also indicates DTP vaccine and hepatitis B vaccine at birth, one month, and three months, and measles vaccine at 10 months of age. She received a dose of inactivated influenza vaccine five weeks ago at a local pharmacy. It was the first time she had ever received influenza vaccine. Here are three questions about Raysa. What vaccines or vaccines does she need today? Does she have any contraindications to any of the vaccines she needs today? When should Raysa return and what vaccine or vaccines should she receive at the next visit? If you're viewing this program with a group we suggest you pause the program now and discuss it among yourselves. We'll return in just a moment to discuss it with you. Children adopted from outside the United States often have written records of the vaccines they received in their home country. Whether or not these records accurately reflect the vaccine the child actually received is another issue that we'll not discuss today. For Raysa we will assume her vaccination record is accurate. So the first task is to look at the spacing and timing of the vaccines in her written record to determine which doses can be counted as valid. Here then is the first question about Raysa. What vaccines does she need today? Now keep in mind that what Raysa needs and what she can receive may not be the same. Today Raysa needs DTAP, Hepatitis B, IPV, Hib, pneumococcal congeal vaccine, MMR, and varicella vaccine. Since five weeks have passed since her first dose of influenza vaccine she should also receive her second dose now. She also needs Hepatitis A vaccine if your Stader County is doing a catch-up Hepatitis A vaccination program. Once again you'll need to consult good old table one in the general recommendations on immunization to evaluate the timing and spacing of the vaccine doses that she received in Russia. The minimum age for DTP or DTAP vaccine is six weeks. So the doses she received at birth in one month of age are invalid. The dose at three months is her first valid dose of DTP so you'll give her DTAP today and count it as the second valid dose. The minimum age for polio vaccine in the United States is also six weeks so the OPV she received at birth in one month are also invalid. The doses at three and four months are valid because they meet the minimum age and the minimum interval between polio doses is four weeks. The IPV you administer today is her third valid dose. She will need a fourth and final dose of IPV at four to six years of age. The doses of Hepatitis B vaccine at birth in one month of age are valid but the dose at three months is not valid because the minimum age of the third dose of Hepatitis B vaccine is 24 weeks. The Hepatitis B vaccine dose you administer today will complete the series. Since RACA needs DTAP, IPV, and Hepatitis B vaccines today you could administer all of them in one shot using pedia ricks. In fact you will probably appreciate this because of all the other injected vaccines she needs at this visit. RACA has no record of having received Hib or pneumococcal conjugate vaccine and she needs them both so you administer her first and only dose of Hib and the first of two doses of PCV. A month has passed since her first dose of influenza vaccine so you can administer the second dose today. Her first Hepatitis A vaccine can be given again if your state or county has a Hepatitis A vaccination ketchup program for children. Finally her single antigen measles vaccine was given at 10 months of age that's two months earlier than the minimum age in the U.S. So she needs MMR. Without a history of chicken pox she also needs varicella vaccine. But should she receive them today? That brings us to the second question for RACA. Does she have any contraindications to the vaccines she needs today? Yes she does. The T lymphocyte percentage is a contraindication for MMR and varicella vaccines. Both MMR and varicella vaccines are recommended for persons with HIV infection but only those who are not severely immunocompromised. For children severe immunocompromised is considered to be present when the CD4 T lymphocyte percentage is 15 percent or lower. RACA's most recent CD4 count was 12 percent so she should not receive MMR and varicella vaccines today. Her HIV infection regardless of CD4 count is also a contraindication to live attenuated influenza vaccine. So today she should receive inactivated influenza vaccine. RACA can receive all the inactivated vaccines she needs. Here is the third question about RACA. When should she return and what vaccines should she receive at the next visit? RACA should return in four weeks for her second dose of DTAP. She will need to return in eight weeks for her second dose of pneumococcal conjugate vaccine. For healthy unvaccinated children a single dose of PCV is recommended after 24 months of age or older but RACA's HIV infection puts her at increased risk for pneumococcal disease so she should receive a second dose eight weeks after the first dose. She'll also need pneumococcal polysaccharide vaccine at least eight weeks after the second dose of PCV. Now it is likely that RACA will be started on antiviral drug therapy for her HIV infection. Her CD4 percentage is likely to improve with this therapy so you will need to stay in close contact with whoever is managing her HIV drug therapy. Once her CD4 percentage rises above 15 percent you will be able to administer MMR and varicella vaccines. You will need to administer these vaccines as separate vaccines since MMRV is not approved for children with HIV infection. Andrew. Bill, thank you. Great case. Just a quick follow-up question. You mentioned Rice as a candidate for pneumococcal polysaccharide vaccine. Is that given her medical history or how do you schedule out those doses? Yes, she would be considered high risk for pneumococcal disease because of HIV infection which fortunately doesn't seem to be symptomatic now but she would still fall into the indications for both pneumococcal conjugate vaccine and pneumococcal polysaccharide vaccine. In these cases you would want to finish her two doses of conjugate vaccine first. They're given at eight week intervals. Then you would then wait another two months before you gave her her pneumococcal polysaccharide vaccine to reduce, presumably reduce the risk of local reactions to the polysaccharide. Great. While we have some time why don't we take some or discuss some questions that we receive frequently. Donna, we're seeing more and more patients that want the MMR vaccine as single antigen vaccines. Are these vaccines available? Yes they are. Either a pharmacist or the healthcare provider can order them from the vaccine manufacturer. Now you know it's a couple of things that need to be discussed with the parent if they're requesting this and that is because these vaccines the single antigens are only available in 10 single dose vials. So that's going to be much more expensive for the provider and they could defer that cost to the parents so each dose could cost that parent several hundred dollars. The other thing is that if you're spreading it out like that then the child is not getting protected against each of these antigens as quickly so they would have to be separated by at least four weeks for each one of these. So in the interim that child is not protected and could become infected and could transmit you know the the virus to someone else. So if this child is like in in daycare you know that could be an issue that they may not allow the child to come to daycare until they're adequately vaccinated. Okay, so another question we receive frequently Bill. If a healthcare provider is born before 1957 and then has a serologic test and tests negative to measles, mumps, or rubella by serology, do they still need to receive MMR vaccine? Yes we've found that that serologic testing particularly of older employees in healthcare facilities medical facilities is actually quite common and unfortunately there will be there will be negatives that turn up. The problem is that doing a screening test for either measles or mumps or rubella or varicella for that matter you can get a negative and you can't really tell whether this could just be indications of waning immunity. The person really did have measles or mumps and just their antibodies below the cutoff level or whether they really are susceptible. There are a few lucky people who managed to not have measles or mumps when they were children in the 50s and early 60s. And since there's no way to tell you really have no alternative but to treat them with the worst case which is to treat them as if they were susceptible in that case then if you have somebody no matter when they're born if they turn up seronegative and they're at high risk healthcare worker for instance or maybe an international traveler. If they're seronegative I don't see that you have any choice but to treat them as if they are truly susceptible and give them two not one but two doses of MMR separated by at least four weeks. Okay Donna we've talked about intervals a lot today and intervals between live live vaccines. What if someone has varicella disease would you then have to wait a period of time 28 days before receiving a measles mumps rubella vaccine? No you don't have to wait the interval between disease and giving the vaccine like you would you know you need to wait 28 days between a dose of varicella vaccine and a dose of MMR vaccine that are not given simultaneously because it could interfere with the the replication of the vaccine virus and response to the vaccine but that that same thing does not occur with the disease so you don't have to wait. You don't have to wait. No you just wait until they're you know no longer ill. And how do you define what that means is that when lesions crust over or how would you define? Well actually that's probably a good way to define it is because that's usually when we say that kids can go back to school is once all of the lesions are crusted over and no new lesions are occurring so you could use that as your definition of no longer being acutely ill so that they could receive the vaccine. Bill we've we talked a bit about HIV today are there circumstances since there are circumstances when you can give a child with HIV MMR vaccine why is it that they can't receive the MMRV vaccine? You know it's a it's primarily a licensure issue when Merck did the trials for MMRV that led to it being approved they did not include any children who had HIV infection it was all healthy kids through age 12 up to age 13 so basically there's no safety data at all and there is concern this is not just plain varicella there's concern because there's so much more varicella virus in MMRV that this could create a safety issue for the child so until more data is available we'd rather not expose those kids to MMRV and just use single antigen varicella and MMR separate. Okay Donna we have about a minute left another quick question about the MMRV vaccine what if someone older than 12 years of age and inadvertently receives the MMRV vaccine? Well if that happens don't do it again because it is medication error but you don't have to repeat the dose you know it was not studied in in that age group and an older person so we don't you know you shouldn't use it that way but we have no reason to think that they would not respond to the vaccine so you can count the dose but don't do it again and we do suggest maybe that you go ahead and mark those baskets in the refrigerator or the shelves where you keep the vaccines in the refrigerator with the age group so that you you don't get them mixed up. Well thank you Donna thank you Bill. Okay in this segment of the program we will discuss varicella or chickenpox, herpes zoster and varicella vaccines. Those of you with inquiring minds may have wondered about the origin of the term chickenpox. What do chickens have to do with a rash illness? Well as it turns out nothing. The name chickenpox comes from chickpeas. The name refers to the similarity between a varicella skin lesion and a chickpea or garbanzo bean. The term chickenpox first appeared in the medical literature in 1694 but had probably been in common use long before then. Herpes zoster or shingles has been recognized for hundreds of years. The name shingles is from the Latin word singulum meaning girdle. Varicella was not differentiated from smallpox until the end of the 19th century. The association between varicella and zoster was deduced in 1888 when it was observed that chickenpox resulted when children were exposed to persons with zoster. The virus was not isolated until 1958. Varicella zoster virus or VZV is a member of the herpes virus family. Other members include herpes simplex one and two, cytomegalovirus and epstein bar virus. VZV shares with these viruses the capacity to persist in the body after primary infection and a tendency to recur. The primary or initial infection with VZV results in varicella or chickenpox. Recurrent infection results in herpes zoster or shingles. The virus is fragile and survives only a short time in the environment. The incubation period of varicella is usually 14 to 16 days but may be as long as 21 days. There may be a mild prodrome for one to two days followed by several successive crops of puritic vesicles. Lesions first appear on the head but are usually most concentrated on the trunk. Almost all primary infections with varicella zoster virus are symptomatic. Subclinical or asymptomatic primary infections are unusual. However, there may be only a few lesions which may be overlooked by the patient or the parent. But a mild case of varicella seems to result in the same immunity as a severe case with hundreds of lesions. The majority of persons will have a single episode of chickenpox but second episodes of chickenpox have been reported. The frequency of these repeated episodes is not known with certainty. One investigation found that as many as 13 percent of persons with chickenpox reported a prior history of chickenpox. Herpes zoster or shingles is caused by a reactivation of a latent varicella zoster virus infection. This can occur years or even decades after illness with chickenpox. It is generally associated with normal aging and with anything that causes reduced immunocompetence such as immunosuppressive drugs, cancer, or infections like HIV. It can occur in healthy children and younger persons but this is less common. More than half of the cases occur in persons 60 years and older. Zoster is a common illness with an estimated lifetime risk of 32 percent in the United States. 50 percent of persons living until 85 years of age will ultimately develop zoster. An estimated one million cases of zoster occur annually in the U.S. Zoster is characterized by a unilateral vesicular rash and pain that is usually limited to a single dermatone on the trunk. It can be very painful. There may be pain, numbness, or tingling of the area two to four days before the rash appears. Pain or numbness usually resolves within weeks but it can sometimes persist for much longer. Damage can occur to the eyes or other organs if they are involved. Varicella virus may be transmitted from the lesions of patients with zoster. Transmission of varicella virus from a person with zoster to a susceptible person results in chickenpox, not zoster. A person who has already had varicella does not develop shingles if exposed to a person with chickenpox. Most of you have seen varicella but here's a short video to illustrate some of the most characteristic features. This child has chickenpox, the primary infection with varicella zoster virus. This girl has typical vesicular lesions on the face. The lesions are fairly widespread but are typically more concentrated on the trunk. This is a few days later. Notice that some of the lesions are beginning to crust. This is a close-up of the vesicular lesions of varicella. There are lesions in various stages of evolution from macules to fully developed vesicles. Umbilicated skin lesions are not common in varicella but are often seen in smallpox. This child has herpes zoster or shingles involving her fifth cranial nerve. Zoster involving this nerve root may affect the eye. This is typical herpes zoster involving a unilateral thoracic nerve root. Herpes zoster is typically very painful. There may be pain even after the lesions resolve a condition known as post-herpetic neuralgia. An episode of zoster typically lasts about two weeks but the skin may not return to normal for up to a month. Varicella is generally not a serious illness in healthy children but may result in complications. The most common complications are bacterial infection of lesions. This complication can be very severe or fatal particularly if group A streptococcus is involved. Central nervous system manifestations such as cerebellar ataxia and encephalitis are not common occurring in one in 4,000 and one in 100,000 cases respectively. Pneumonia may occur after varicella among adults or children. Hospitalization occurs in 3 to 4 per 1,000 cases. However because of the huge number of cases this amounted to 11,000 hospitalizations from varicella per year in the pre-vaccine era. Death occurs in about one in 60,000 cases which meant up to 100 deaths per year in the pre-vaccine era. About 67 percent of hospitalizations and 50 percent of deaths occurred in healthy children. Many providers consider varicella to be a trivial disease, more of a nuisance than a serious health threat. While it is true that many cases are relatively mild, 100 deaths a year and 11,000 hospitalizations in the pre-vaccine era was not indicative of a trivial disease. The message here is that varicella and its complications can be dangerous, all the more reason to prevent it with vaccine. Some groups are at increased risk for complications of varicella. For example, healthy adults are 25 times more likely to die from varicella than healthy children. Although adults make up only about 7 percent of varicella cases, they account for most varicella deaths. Of the 16 varicella-related deaths in 2003, 15 were adults 20 years of age or older. Adults are often infected by their unvaccinated children. Immunocompromised persons are at high risk of severe varicella disease. These persons may have prolonged illness and an increased risk of complications. One of the highest risk groups is newborns of mothers with rash onset within five days before to two days after delivery. The fetus receives an intravenous exposure to varicella virus through the umbilical cord and is then born without the benefit of its mother's antibody. These children often develop severe varicella and are one of the most important groups for post-exposure prophylaxis with a varicella antibody-containing product. Zoster can also have complications. A feared consequence of zoster, particularly in older persons, is post-repaec neuralgia or pHN. pHN is the persistence of sometimes debilitating pain weeks to many months after resolution of the rash. Approximately 15% of zoster cases involve the ophthalmic division of the trigeminal nerve and involve the eye. This is called ophthalmic zoster and can lead to reduced vision or blindness. Life-threatening complications of zoster can occur. These include dissemination with generalized skin eruptions and involvement of the central nervous system, lungs, liver, and pancreas. Dissemination, pneumonia, and visceral involvement are, however, usually restricted to immunocompromised persons. Complications of herpes zoster, particularly post-herpaec neuralgia, can have a major impact on the quality of life of older adults. Chronic pain from zoster can lead to insomnia, depression, and poor physical and social functioning. There is no consistently effective treatment for pHN. Bill? The number of cases of varicella is declining, but the disease remains endemic in the United States. However, the widespread use of varicella vaccine is changing the epidemiology of varicella. Varicella is a human disease and the reservoir is humans with acute and chronic infection. These chronic infections will make eradication very difficult. The disease is transmitted by airborne droplets or by direct contact with the lesions of either chickenpox or zoster. Varicella is communicable from one to two days before until four to five days after onset of rash when all the lesions are crusted. Immunosuppressed persons with varicella may transmit longer. Varicella is very contagious with a secondary attack rate of 90% or higher in households. In the pre-vaccination era, an estimated 3 to 4 million cases of varicella occurred every year, basically the entire annual birth cohort. 85% of all cases of varicella occurred in children younger than 15 years of age. The good news is that vaccination coverage among children has risen steadily and fewer cases of chickenpox are now being reported. In 2006, varicella vaccination coverage for U.S. children 19 to 35 months of age, as estimated by the National Immunization Survey, was 89%. As vaccination coverage has increased, the number of cases has decreased. Currently, most of the detailed information about the change in varicella epidemiology, including reduced disease incidents by age group, comes from two active surveillance sites in Antelope Valley, California and West Philadelphia, Pennsylvania. These sites were established in 1995 to monitor the impact of the vaccination program because national surveillance for varicella did not exist at the time of vaccine licensure. Vaccination coverage in the active sites has risen from 40% in 1997 to greater than 90% in 2006. Reduction in varicella incidents has been observed in all age groups in both of the active surveillance sites. The greatest reduction has been seen in children 1 to 9 years of age and adolescents 10 to 14 years of age. The number of outbreaks and the number and rates of hospitalization have also declined. The overall reduction in varicella since the availability of vaccine is not unique to the active surveillance sites. Among the states that have consistently reported cases through the National Notifiable Disease Surveillance System, there has also been a significant reduction in cases compared to the pre-vaccine era. Nationally, varicella hospitalizations and deaths have also declined substantially, especially among children. In this age group, there has been a decline of 90% or greater. The epidemiology of varicella has changed since the vaccine was licensed in 1995. As anticipated, the proportion of cases among vaccinated persons has increased and the median age of patients has shifted toward adolescents. So now it's increasingly important to ensure that older children, adolescents and adults are vaccinated. High one-dose vaccination coverage and success of the vaccination program has reduced varicella morbidity and mortality, but reports to CDC from states with well-implemented vaccination programs and surveillance and the active surveillance sites indicate that the number of reported varicella cases has not changed substantially in the last five to six years. From 2001 to 2005, outbreaks of varicella were reported in schools with one-dose varicella vaccination coverage as high as 96% to 100%. The outbreaks were similar in that all occurred in elementary schools. Vaccine effectiveness was within the expected range of 72% to 85% and the highest attack rates occurred among the younger students. In addition, each outbreak lasted about two months and vaccinated children played a role in transmission although their disease was mild. Overall, attack rates among vaccinated children ranged between 11% and 17% with attack rates in some classrooms as high as 40%. These data indicate that even in settings where almost everyone had received one dose and the vaccine performed as expected, varicella outbreaks could not be prevented. Donna. There are now three varicella-containing vaccines available in the United States. Single antigen varicella vaccine was licensed in the United States in 1995. Combination, measles mumps rubella varicella vaccine or MMRV was licensed in 2005 for children 12 months through 12 years of age. Zoster vaccine was licensed in 2006. We will discuss zoster vaccine in more detail a little later. All three vaccines contain the same live Oka-Merc varicella vaccine virus, but in different amounts. The concentration of virus is measured in plaque-forming units abbreviated as PFU. Varivax single antigen varicella vaccine contains about 1400 PFU per dose. Proquod or MMRV contains about 9,800 PFU per dose, about seven times the virus in a dose of varivax. Zoster vaccine contains 19,000 PFU per dose, about 14 times the concentration in varivax. MMRV contains more varicella vaccine virus than varivax in order to overcome a reduced varicella seroconversion rate when mixed in the same syringe as MMR vaccine. Zoster vaccine contains much more vaccine virus than either varivax or MMRV because it is administered to immune persons and a larger virus dose is needed to overcome this immunity. The efficacy of one dose of single antigen varicella vaccine has been estimated at 70 to 90 percent against infection and 95 percent against severe disease. Vaccine efficacy estimated in clinical trials has been verified in investigations of varicella outbreaks. A clinical trial of single antigen varicella vaccine estimated the efficacy of two doses against infection for a 10-year period as 98 percent. This was significantly higher than efficacy after one dose. The two-dose regimen was 100 percent efficacious against severe varicella. One of the most common concerns we hear about varicella vaccine has to do with waning immunity and breakthrough disease. Breakthrough disease is not unique to varicella vaccine but seems to draw more attention for some reason. Varicella breakthrough is defined as varicella in a previously vaccinated person more than 42 days after vaccination. Breakthrough disease usually is much milder than varicella in an unvaccinated person. A person with breakthrough disease usually has fewer than 50 lesions. Breakthrough disease can occur in up to 30 percent of recipients of one dose of varicella vaccine. Many studies have attempted to identify risk factors for breakthrough disease. Some but not all have found an increased risk with increasing time since vaccination and younger age of vaccination but no consistent risk factors have been identified in these studies. In 2001 the national immunization program conducted a study using the vaccine safety data link system to investigate risk factors for varicella breakthrough disease. This study found that children who received varicella vaccine less than 30 days after MMR vaccination had a significantly increased risk of breakthrough varicella compared to those who received varicella vaccine before simultaneous with or more than 30 days after MMR. These findings support the current recommendation for the non-simultaneous administration of injected or intranasal live virus vaccines. If varicella vaccine is not administered on the same day as MMR or live attenuated influenza vaccine the vaccines should be separated by at least four weeks. If these live vaccines are not given on the same day but are separated by less than four weeks ACIP recommends that the vaccine given second should be repeated. This recommendation is because of the possibility of interference from the vaccine given first with the vaccine given second. The repeat dose should be given four weeks after the vaccine given second. As we discussed earlier outbreaks of varicella have been documented in schools with very high one-dose varicella vaccination levels. These outbreaks occur because from 10 to 30 percent of one-dose recipients may develop breakthrough varicella if exposed and persons with breakthrough disease can transmit varicella virus. The efficacy of two doses of varicella vaccine has been shown to be significantly higher than for a single dose. Laboratory studies have shown that a second dose boosts both humoral and cellular immunity to varicella virus. Finally breakthrough disease is significantly reduced among two-dose varicella vaccine recipients. These observations and the desire to reduce breakthrough disease and the occurrence of varicella outbreaks led to the 2006 recommendation for a second routine dose of varicella vaccine. Andrew? The most current varicella ACIP statement was published in Morbidity and Mortality Weekly Report in June 2007. The two-dose varicella recommendation was also published in the current child and adolescent immunization schedule. All children without contraindications should receive varicella vaccine as a routine vaccination at 12 to 15 months of age. Notice that this is a change from prior recommendations which were for the first dose at 12 to 18 months of age. The vaccine can be given as either single antigen varicella vaccine or MMRV. The new age recommendation is intended to harmonize the varicella vaccine recommendation with that for MMR and to avoid interference with circulating maternal antibody to varicella. Since almost all women of childbearing age in the U.S. have had varicella disease, almost all full-term infants are born with antibody. That is why the vaccine should not be given until at least 12 months of age because of potential interference from circulating maternal antibody. A routine second dose of varicella vaccine is recommended at four to six years of age. This age was chosen to boost varicella immunity prior to school entry and to be consistent with the existing recommendation for a second dose of MMR. This dose can be administered as single antigen varicella vaccine or as MMRV. Two doses of varicella vaccine are recommended for all persons, children and adults older than four to six years of age who do not have evidence of varicella immunity. We will discuss the new definitions of evidence of varicella immunity in a moment. MMRV should not be administered to a person 13 years of age or older. Finally, a second dose of varicella vaccine is now recommended for persons of any age who have only received one dose. Varicella vaccination recommendations are now simple. Preschool age children should receive one dose. Everyone else should receive two doses. Anyone school age or older who has received only one dose should be given a second dose. But there is an important nuance of the new recommendations. The minimum interval between the two doses differs by age. This has been our most common topic of varicella questions in the last few months. For children 12 months through 12 years of age, the minimum interval between doses of varicella vaccine is three months. This is because Merck's data on two doses is based on a three month interval between doses and that is how FDA approved it. For persons 13 years and older, the minimum interval between doses is four weeks as it has always been. There are data on the safety and efficacy of a four-week interval between doses for older persons but little or none for children. In the past, a person of any age with a history of chickenpox could be considered immune to varicella. The 2007 ACIP statement significantly revised the definition for evidence of immunity. The new definitions are more complex than the old definition. If a person meets any one of these criteria, he or she can be considered immune to varicella. The first criterion is written documentation of age-appropriate vaccination. This would be one dose administered on or after the first birthday for preschool-aged children and two doses for school-aged children, adolescents and adults. Second, a person born in the U.S. before 1980 can be considered to be immune except for healthcare personnel and pregnant women. A higher standard of presumptive immunity is needed for these two groups. The third criterion is laboratory evidence of immunity or laboratory confirmation of varicella disease. Commercial assays can be used to assess disease-induced immunity but these assays lack sensitivity to always detect vaccine-induced immunity so they may yield false negative results in vaccinated persons. The fourth criterion is a healthcare provider diagnosis of varicella or verification of history of varicella disease. Verification means that a healthcare provider may retrospectively diagnose chicken pox based on the history provided by a patient or parent. The last criterion for evidence of immunity is a history of herpes zoster or shingles based on a healthcare provider diagnosis. A person needs to fit only one of these criteria to be considered immune to varicella. Anyone who fits none of them should be presumed to be susceptible and should be vaccinated. Details about these criteria for varicella immunity are in the June 2007 varicella ACIP statement. You should make a special effort to assure varicella immunity in adolescents and adults at increased risk of exposure such as teachers, college students, and healthcare personnel. You should also assure immunity in anyone who, if they were to develop varicella, are likely to expose persons at high risk for severe illness. Candidates in this group would include household contacts of immunocompromised persons and healthcare personnel. In 1997, the ACIP published comprehensive recommendations for the protection of healthcare personnel against vaccine-preventable diseases. In this statement, ACIP recommends varicella vaccine for all healthcare personnel without evidence of immunity. Pre-vaccination serologic testing for varicella immunity of certain personnel is probably cost-effective. Screening could be considered for personnel who are uncertain of their varicella history or who claim not to have had the disease. But post-vaccination testing for varicella immunity is not necessary or recommended because 99% of recipients are seropositive after the second dose. In fact, we strongly recommend you not do serologic testing after vaccination. Most commercial antibody tests are not sensitive enough to detect antibody in some vaccinated persons. So post-vaccination testing can make your life more difficult because the false negative results will make it appear that you have more susceptible persons than you actually have. I would like to reiterate that criteria for varicella immunity for healthcare personnel are more stringent than for the general public. Healthcare personnel should be considered immune based only on laboratory evidence of immunity, a history of clinician diagnosed or verified varicella or zoster, or documentation of age-appropriate vaccination with varicella vaccine. Healthcare personnel who do not meet one of these criteria should be vaccinated with two doses of varicella vaccine. A person who meets one of these criteria does not require additional laboratory testing. It is preferable to administer varicella vaccine before a person is exposed to chickenpox, but investigations have shown that varicella vaccine is effective in preventing or modifying the severity of chickenpox if used shortly after exposure. ACIP recommends varicella vaccine for persons without evidence of immunity after exposure to varicella. The vaccine is 70 to 100 percent effective if given within 72 hours and possibly up to five days following exposure. The vaccine is not effective if given more than five days after exposure, but will produce immunity in the recipient if the person has not been infected with wild varicella virus. The exposure to varicella results in infection. There is no evidence to indicate that administration of varicella vaccine before onset of illness increases the severity of disease or the risk of vaccine adverse reactions. Bill? The contraindications to varicella vaccine are very similar to those for other live virus vaccines. As usual, a severe allergic reaction to a vaccine component or following a prior dose of vaccine is a contraindication. For varicella vaccine, this would include severe allergy to neomycin and gelatin. Varicella vaccine does not contain egg protein. Pregnancy and immunosuppression are also contraindications to vaccination. Since licensure in 1995, varicella vaccine like other live virus vaccine have been contraindicated in persons with significant immunodeficiency from any cause, but varicella vaccine is somewhat different than other live virus vaccines. Most immunocompromised persons should not be vaccinated, but available data indicate that varicella vaccine is both effective and safe in persons with impaired humeral immunity. This includes persons with hypogamma globulinemia and other selective B cell immune deficiencies. Humeral immunodeficiency alone is not considered to be a contraindication to varicella vaccine. ACIP now recommends that you routinely vaccinate persons with isolated humeral immunodeficiency. But remember that the antibody products used to treat and isolated humeral immunodeficiency may interfere with the response to the vaccine. We'll come back to this issue in a moment. Data from a clinical trial among children with asymptomatic or mildly symptomatic HIV infection showed that two doses of vaccine was both immunogenic and effective. Persons with HIV infection are at increased risk of morbidity from varicella and herpes zoster. The ACIP recommends that clinicians consider varicella vaccination for HIV infected children. Specifically, this recommendation includes children with an age-specific CD4 T lymphocyte percentage of 15% or higher. Eligible children should receive two doses of varicella vaccine separated by three months. Please note that MMRV is not approved by FDA for use in HIV infected children. HIV testing prior to vaccination with varicella vaccine is not necessary or recommended. Data on the use of varicella vaccine in HIV infected adolescents and adults are lacking. However, on the basis of expert opinion, the safety of varicella vaccine in HIV infected persons eight years of age and older with comparable levels of immune function is likely to be similar to that of children younger than eight years of age. But immunogenicity may be lower in older HIV infected children, adolescents, and adults compared to younger children. But the potential benefit of vaccination and prevention of severe disease caused by wild type varicella virus likely outweighs the hypothetical risk from the vaccine. As a result, ACIP now recommends that clinicians consider varicella vaccination for HIV infected older children and adults with a CD4 T lymphocyte count of 200 cells per microliter or higher. As with children, these persons should receive two doses of varicella vaccine separated by three months. If the vaccinated person develops an adverse reaction such as a fever or severe rash, a cyclovir or other drug with activity against herpes viruses might reduce the severity of the symptoms. Varicella vaccine is also recommended for administration to healthy household contacts of an immunosuppressed person. The rationale is if the healthy household contact is not immune from varicella from vaccination, he or she may eventually develop varicella disease and expose the immunocompromised household contact to a much greater risk from the wild type virus. Merck and CDC have maintained a varicella vaccination in pregnancy registry since the vaccine was licensed in 1995. As of 2005, more than 900 women vaccinated during or near pregnancy have been enrolled. To date, there is no evidence of injury or defects attributable to varicella vaccine in any of the infants born to these women. This, of course, does not rule out the possibility of a very small risk to a fetus. ACIP recommends that women known to be pregnant not receive varicella vaccine. Women should be advised to avoid pregnancy for one month after receiving varicella vaccine. You should be aware that the package insert suggests a three-month avoidance of pregnancy. Also note a pregnant household contact is not a contraindication to vaccination of a healthy child. As with all vaccines, moderate or severe acute illness is a precaution. Vaccination should be deferred until the acute illness has improved. Finally, a recent blood product could interfere with viral replication. The recommendation is to administer the vaccine at least two weeks prior to receiving blood products. Vaccination should be delayed for at least three months following administration of blood, immune globulin, or other blood product. The interval depends on the type of blood product. A table listing these intervals is in the general recommendations on immunization and available on the updates and resources webpage. If the interval between the blood product and the vaccine is less than three months, you should repeat the dose after the appropriate interval has elapsed. Varicella vaccine is usually very well tolerated and significant adverse reactions are not common. The most common adverse reaction is an injection site complaint such as pain, swelling, and redness. You might not have expected this from a live virus vaccine, but injection site complaints are reported in about 20 percent of recipients. Three to four percent of recipients will develop a varicella-like vesicle at the site of injection. Generalized rash is reported in four to six percent of recipients. The rash may be maculopapular rather than vesicular and has an average of only five lesions. A temperature of 102 degrees Fahrenheit or higher in the 42 days following varicella vaccination was reported by 10 to 15 percent of recipients. The rates of some adverse reactions following the first dose of combined MMRV are higher than when MMR and varicella vaccines are administered separately at the same visit. In clinical trials, a generalized measles-like rash was reported in three percent of MMRV recipients compared with two percent of children receiving MMR and varicella vaccines separately. Fever of 102 degrees in the 42 days following vaccination was reported in 22 percent of MMRV recipients compared with 15 percent of children receiving separate injections. Preliminary results from a study from the Vaccine Safety Data Link reported that while febrile seizures following MMR and varicella vaccination are not common, they occurred almost twice as often among recipients of MMRV, nine per 10,000 children vaccinated, than among children who received separate injections of MMR and varicella, four per 10,000 children vaccinated. The ACIP is currently evaluating these data to determine what, if any, change to make in its recommendation for use of MMRV. Varicella vaccine virus probably produces a latent infection in some vaccine recipients, probably those recipients who develop a vaccine associated rash. So, herpes zoster would be expected to occur in vaccine recipients, and there have been a few reports of herpes zoster in vaccine recipients. Most cases of zoster after vaccination have been reported in children. This would make sense since most vaccine has been given to children. Vaccine virus has been isolated from only a few of these children. Wild type varicella virus has been isolated in some cases, meaning that the person was infected with the wild type varicella before or after being vaccinated. Based on current data, the risk of zoster from the vaccine virus appears to be less than the risk of zoster from the wild varicella virus. In addition, zoster after vaccine has been mild without complications such as post-herpetic neuralgia. The risk of zoster following infection with wild type varicella virus increases with increasing age. Whether this will be the case with zoster following infection with vaccine virus is not known at this time. This is another varicella vaccine issue that will be carefully monitored for many years in the future. Andrew. Concerns about vaccinating healthy household contacts of immunosuppressed persons or pregnant women are due to fears of transmission of vaccine virus. There have been reports of transmission of vaccine virus, but this appears to be a rare event. Studies of household contacts of vaccinated persons have demonstrated that asymptomatic transmission of vaccine virus may occur. Household contacts have been observed to develop varicella antibody without having been vaccinated or having chickenpox. It appears that the risk of transmission is increased if the recipient develops a rash following vaccination. In fact, transmission may only occur when the recipient develops a rash. So if a vaccinated child develops a rash, it is recommended that close contact with susceptible persons at high risk of complications of varicella such as immunocompromised persons be avoided until the rash resolves. We discussed vaccine storage and handling in the first session of this course. Because varicella and MMRV vaccines are particularly fragile, we would like to remind you of their storage requirements. Varicella and MMRV vaccines must be kept frozen. They must be shipped with dry ice and must be stored at five degrees Fahrenheit or colder. Varicella and MMRV vaccines should only be stored in freezers or combination refrigerator freezers with separate compartments that each have a separate external door. If optimal handling conditions for varicella vaccine are not feasible, or the vaccine is to be transported to a distant site, the vaccines may be stored up to 72 hours at refrigerator temperature, which is 35 to 46 degrees Fahrenheit. But any unused vaccine cannot be refrozen and must be discarded after 72 hours at this temperature. Varicella and MMRV vaccines must be administered within 30 minutes of reconstitution. If not used within 30 minutes, the vaccine should be discarded. Please be sure everyone in your office is familiar with the storage and handling of MMRV. You never want to make storage in handling or administration errors. At more than $100 a dose, this error would be very expensive. Varicella zoster immune globulin, known as VZIG, is a hyperimmune human antibody product. It is used for post-exposure prophylaxis of varicella of certain groups, such as immunocompromised persons and infants born to women with onset of varicella shortly before or after delivery. The sole U.S. licensed manufacturer ceased production of VZIG in 2005, and the U.S. supply is now depleted. A Canadian manufacturer is currently supplying VZIG for the U.S. market. The product is called Verizig. However, the product is in investigational drug status until it can be licensed by FDA. Information on the use of Verizig is included as a footnote to Table 4 of the 2006 general recommendations on immunization. An MMWR article concerning Verizig was published in March 2006. We will include a link to the MMWR article on the Updates and Resources webpage. Herpes zoster, or shingles, has been recognized as a clinical condition for hundreds of years. The name shingles is from the Latin word singulum, meaning girdle. The association between varicella and zoster was deduced in 1888 when it was observed that chickenpox resulted when children were exposed to persons with zoster. Herpes zoster, or shingles, is caused by a reactivation of a latent varicella zoster virus infection. This can occur years or even decades after illness with chickenpox. It is generally associated with normal aging and with anything that causes reduced immunocompetence, such as immunosuppressive drugs, cancer, or infections like HIV. It can occur in healthy children and young adults, but this is less common. More than half the cases occur in persons 60 years and older. Varicella virus may be transmitted from the lesions of patients with zoster. Transmission of varicella virus from a person with zoster to a susceptible person results in chickenpox, not zoster. A person who has already had varicella does not develop shingles if exposed to a person with chickenpox. Zoster is a common illness with an estimated lifetime risk of 32 percent in the United States. 50 percent of persons living until 85 years of age will ultimately develop zoster. An estimated one million cases of zoster occur annually in the U.S. Zoster is characterized by a unilateral vesicular rash and pain that is usually limited to a single dermatome on the trunk. It can be very painful. There may be pain, numbness, or tingling of the area two to four days before the rash appears. Damage can occur to the eyes or other organs if they are involved. The rash usually lasts seven to ten days with complete healing within two to four weeks. The pain and discomfort associated with herpes zoster can be prolonged and disabling. It can diminish the person's quality of life and ability to function to a degree comparable to that in diseases such as congestive heart failure, type 2 diabetes, and major depression. The most frequent debilitating complication of zoster is post-herpetic neuralgia, a pain syndrome that persists after the dermatomal rash has healed. The frequency and severity of post-herpetic neuralgia increase with increasing age. Antiviral therapy can reduce the severity and duration of herpes zoster, but does not prevent the development of post-herpetic neuralgia. Post-herpetic neuralgia may persist for years and is often refractory to treatment. In May 2006, the Food and Drug Administration licensed a new vaccine to reduce the occurrence and severity of herpes zoster and post-herpetic neuralgia. The vaccine is produced by Merck with the brand name Zostavax. Zostavax contains live attenuated varicella virus in an amount that is approximately 14 times greater than that in regular varicella vaccine. Remember that Zostavaxin is administered to people who are immune to varicella because they have had chickenpox. This increased amount of virus in the vaccine was necessary to boost immunity in persons with pre-existing immunity. The vaccine is approved for persons 60 years of age and older. Like other varicella-containing vaccines, Zostavax is administered by the subcutaneous route. The current FDA licensure and ACIP recommendation is for a single dose of Zostavaxin. The duration of protection or need for more than one dose is not known at this time. Studies are in progress to assess the duration of immunity and need for more than one dose. The pivotal clinical trial for Zostavaxin included more than 36,000 adults 60 years of age and older. Half the participants received vaccine and half received placebo. All participants were followed for more than three years. Compared with the placebo group, the vaccine group had 51% fewer episodes of Zostar. Those who did develop Zostar had less severe disease. Vaccine recipients also had 66% less post-herpatic neuralgia. The pain that can persist long after the shingles rash has resolved. No significant safety issues were identified in the trial. The most common adverse reactions in persons who received Zostar vaccine were local reactions at the site of injections such as redness, pain and tenderness, swelling and itching. The ACIP recommendations for Zostar vaccine were published in MMWR in June 2008. This document contains detailed information about Zostar and the vaccine. The ACIP recommendation is for a single dose of Zostar vaccine for adults 60 years of age and older whether or not they report a prior episode of shingles. Off-label use of Zostar vaccine in persons younger than 60 years is not recommended. Persons with a chronic medical condition may be vaccinated unless a contraindication or precaution exists for their condition such as immunosuppression. We'll come back to contraindications and precautions in a moment. Since Zostar vaccine was licensed, the most common question we have received from the public is where they can get a dose. The most common question from providers is use of Zostar vaccine in a person who has a history of shingles. We have even been asked if Zostar vaccine can be administered during a case of shingles. In theory, a case of Zostar will cause an immunologically normal person to boost their immunity to varicella virus. This should reduce the person's risk for another occurrence of shingles for some time afterward. But there are no data to determine if this actually occurs and if it does for how long. Also, many cases of shingles are self-diagnosed or misdiagnosed by clinicians. Because of this uncertainty, ACIP decided to recommend Zostar vaccine for persons 60 years or older, regardless of their previous history of shingles. There is no evidence that Zostar vaccine has any therapeutic value. There is no evidence that it will benefit a person who currently has shingles. Vaccination should be deferred for a person with shingles until their acute illness has improved. The availability of Zostar vaccine has also raised many questions from clinicians about the need to determine the person's past history of varicella, either by obtaining a history of chicken pox or by serologic screening for varicella antibody. Neither of these is necessary. Screening for a history of varicella disease is not necessary or recommended in order to administer Zostar vaccine to a person 60 years of age or older. Persons born in the United States before 1980 can be assumed to have had chicken pox regardless of their recollection of chicken pox. Since the vaccine is approved only for persons 60 years and older, all potential vaccine recipients will have been born before 1980, so you do not need to inquire about their history of chicken pox. Please note that this definition of varicella immunity applies only for determination of Zostar vaccine eligibility. Birth before 1980 does not establish varicella immunity for healthcare personnel. This issue is discussed in more detail in the varicella segment of this program. Also, you should not test the person for varicella antibody regardless of their history of chicken pox. Although most persons 60 and older will test positive, since they had chicken pox, some will test negative. A negative screening test is more likely to indicate waning antibody level below the detection limit of the test, rather than true susceptibility. Persons who are tested and found to be seronegative should receive two doses of single antigen varicella vaccine, not Zostar vaccine. Zostar vaccine is not currently indicated for a person whose immunity is based on vaccination. So make your life easier and do not screen potential Zostar vaccine recipients for either a history of chicken pox or do serologic testing for varicella immunity. It is not necessary, but you must screen for true contraindications to Zostar vaccine. Contraindications and precautions for Zostar vaccine are similar to those for other live virus vaccines. What makes Zostar vaccine different is that it is being administered to persons who are 60 years of age and older and who are already immune to varicella. As with all vaccines, a severe allergic reaction to a vaccine component or following a prior dose is a contraindication. Pregnancy or planned pregnancy within four weeks and immunosuppression are contraindications to vaccination. We have received many questions about immunosuppression and Zostar vaccine, so we will expand on this issue for a moment. Zostar vaccine should not be administered to persons with primary or acquired immunodeficiency. This includes persons with leukemia, lymphomas, or other malignant neoplasm affecting the bone marrow or lymphatic system. The package insert implies that Zostar vaccine should not be administered to anyone who has ever had leukemia or lymphoma. However, ACIP recommends that persons whose leukemia or lymphoma is in remission and who have not received chemotherapy or radiation for at least three months can be vaccinated. Other immunosuppressive conditions that contraindicate Zostar vaccine include AIDS or other clinical manifestation of HIV. This includes persons with CV4-T lymphocyte values less than 200 per millimeter or less than 15 percent of total lymphocytes. Persons receiving high-dose corticosteroid therapy should not be vaccinated. High dose is defined as 20 milligrams or more per day of prednisone or equivalent lasting two or more weeks. Zostar vaccination should be deferred for at least one month after discontinuation of therapy. As with other live viral vaccines, persons receiving lower doses of corticosteroids may be vaccinated. Topical inhaled or intraarticular steroids or long-term alternate day treatment with low to moderate doses of short-acting systemic corticosteroids are not considered to be sufficiently immunosuppressive to contraindicate Zostar vaccine. Also, low doses of drugs used for the treatment of rheumatoid arthritis, inflammatory bowel disease and other conditions such as methotrexate, azothioprine or six mercaptopurine are also not considered sufficiently immunosuppressive to create safety concerns for Zostar vaccine. Low dose therapy with these drugs is not a contraindication for administration of Zostar vaccine. The experience of hematopoietic stem cell transplant recipients with varicella-containing vaccines, including Zostar vaccine, is limited. Physicians should assess the immune status of the recipient on a case-by-case basis to determine the relevant risks. If a decision is made to vaccinate with Zostar vaccine, the vaccine should be administered at least 24 months after transplantation. Finally, regarding recombinant human immune mediators and immune modulators, in particular, the anti-tumor necrosis factor agents at a limumab, infliximab and etanercept, the safety and efficacy of Zostar vaccine administered concurrently with these agents is not known. It is preferable to administer Zostar vaccine before treatment with these drugs. If it is not possible to administer Zostar vaccine to patients before initiation of treatment, physicians should assess the immune status of the recipient on a case-by-case basis to determine the relevant risks and benefits. Otherwise, vaccination with Zostar vaccine should be deferred for at least one month after discontinuation of treatment. As with all vaccines, moderate or severe acute illness is a precaution to vaccination. Current treatment with an antiviral drug active against herpes viruses, such as acyclovir, fam-cyclovir or valacyclovir, is a precaution to vaccination. These drugs can interfere with replication of the vaccine virus. Persons taking these drugs should discontinue them at least 24 hours before administration of Zostar vaccine, and the drug should not be taken for at least 14 days after vaccination. Unlike most other live virus vaccines, recent receipt of a blood product is not a precaution for Zostar vaccine. Zostar vaccine can be administered at any time before, concurrent with or after receiving blood or other antibody-containing blood products. Persons with a history of varicella are immune and generally maintain a high level of antibody to varicella Zostar virus, a level comparable to that found in donated blood and antibody-containing blood products. Receiving an antibody-containing blood product will not change the amount of antibody in the person's blood. Like regular varicella vaccine, Zostar vaccine must also be stored at freezer temperature, 5 degrees Fahrenheit or colder at all times. Vaccine not stored at this temperature should not be administered. Before reconstitution, the vaccine should also be protected from light. It must be administered within 30 minutes of reconstitution or must be discarded. Practices that see both children and adults may now have both varicella and Zostar vaccines in their freezer. You must be very careful to not inadvertently administer Zostar vaccine to a child or varicella vaccine to an adult. The 2008 Zostar vaccine ACIP statement is a comprehensive document that contains more details than we can include on this program, particularly for the issue of immunosuppression. If you administer Zostar vaccine in your practice, you will find the ACIP statement very helpful. We will include a link to the statement on the program updates and resources web page. We would like to present a case study that addresses issues that we have discussed during this program. The case studies are available on the updates and resources web page for this program. Our second case study is Hank. Hank is a 61-year-old retired aerospace engineer beginning a second career as an aide in a children's hospital. He has a history of psoriatic arthritis diagnosed six months ago. The arthritis is being treated twice a week with etanercept, also known as inbrel. Hank had severe varicella at age 22 that was complicated by varicella pneumonia and required hospitalization. He also reports a mumps outbreak in the community served by the hospital. Several children with mumps have recently been admitted to the hospital where he works. Here is Hank's vaccination history. His childhood vaccination record was lost in a fire several years ago. One month ago, he received inactivated influenza vaccine and his third dose of hepatitis B vaccine. One year ago, he received a dose of adult TD and a dose of MMR. These are his only documented doses of both vaccines. Here are the questions about Hank. What vaccine or vaccines does Hank need today? Are there any contraindications to the vaccine or vaccines he needs today? Is any serologic testing indicated for Hank? If you are viewing this program with a group, we suggest you pause the program now and discuss it among yourselves. We will return in a moment to discuss it with you. Vaccines are often indicated by a person's age, the presence of underlying medical conditions or treatment of those conditions, and a person's occupation. In Hank's case, all of these are factors. Further complicating the issue is the presence of a mumps outbreak in the community. Here is the first question about Hank. What vaccine or vaccines does Hank need today? Now remember that what vaccines a person needs and what they can receive may be different. Hank should receive a dose of TDAP today. Both brands of TDAP are now licensed for use in persons through 64, so Hank may receive a dose of either brand. A second dose of MMR would be indicated even though Hank was born before 1957. Zoster and pneumococcal polysaccharide vaccines are also indicated. In 2006, ACIP revised recommendations for mumps immunity. During an outbreak, ACIP recommends that medical facilities strongly consider recommending two doses of mumps vaccine for unvaccinated healthcare personnel born before 1957 who do not have evidence of mumps immunity. At 61 years of age, Hank is also eligible for a dose of Zoster vaccine. Etanercept is an immunosuppressive drug, so Hank should also receive a dose of pneumococcal polysaccharide vaccine. Here is the second question about Hank. Are there any contraindications for the vaccines he needs today? Yes, the etanercept Hank is receiving for his psoriatic arthritis is a contraindication to MMR and Zoster vaccines. Etanercept may be immunosuppressive. The ACIP recommends that until additional information becomes available, etanercept should be treated like high-dose steroids where live virus vaccines are concerned. Therefore, MMR and Zoster vaccine cannot be given to Hank now. Here is the third question about Hank. Is any serologic testing indicated for Hank? Yes, Hank should be tested for mumps IgG antibody and his response to hepatitis B vaccine with a test for antibody to hepatitis B surface antigen or anti-HBS. He does not need measles antibody testing because one dose of MMR is sufficient evidence of measles immunity for persons born before 1957. If the anti-HBS and mumps IgG are positive, then Hank can be considered immune to hepatitis B and mumps. If the anti-HBS is negative, Hank should receive three more doses of hepatitis B vaccine and then be retested four to six weeks later. If the mumps IgG is negative, Hank should discuss with his treating physician discontinuation of etanercept so the second dose of MMR vaccine can be administered. If the etanercept is discontinued, Hank could receive MMR and Zoster vaccines one month later and Hank will need to come back six months after the TDAP dose for a TD dose to complete his primary series of tetanus and diphtheria toxoids. Andrew? Donna, why does Hank need anti-HBS testing? I thought there were recommendations that stated that post-vaccination testing is not necessary unless an exposure actually occurs. Well, you know, it depends on certain, there are certain people that are more at high risk and because he is a healthcare worker, he should be, it's been four weeks since that third dose, so they should test to make sure that he is immune because if he isn't, then he's going to have to receive a second series. And another question, I guess because we're concerned about a mumps outbreak, Hank needs vaccination. Can he receive single antigen mumps vaccine? No, not now because there is no single antigen measles mumps or rubella vaccines available. Merck is not producing those and we don't know if and when they will again, so the vaccine of choice now to use is the MMR. So MMR vaccine, the only one available? MMR, that's it. Another question, Zoster related question, I'll give to Yabo. We often hear about providers that erroneously give varicella vaccine instead of Zoster vaccine to adults and what do providers need to do if this error occurs? Great question, Andrew. The concern here is that the presumptive criteria is that one is already immune to chickenpox and hence getting the ZosterVax. However, remember that ZosterVax contains 14 times as much varicella antigen as and varicella vaccine. So in theory, this person has not received enough to boost their immunity. The correction here would be in a month, 28 days later to then give the person ZosterVax vaccine. That's a month after the inadvertent administration of varicella vaccine. The converse could also be seen if a child was given ZosterVax instead of varicella vaccine. In that case, the child has already received 14 times more than was recommended. So you would not repeat the varicella vaccine on that day. You would wait for the appropriate age appropriate interval and then give the second dose of varicella vaccine to that child. Great. Great. Thank you very much, Yabo. Thank you, Donna. Diarrheal disease has been recognized in humans since antiquity. Until the early 1970s, a bacterial, viral or parasitic etiology of diarrheal disease in children could be detected in fewer than 30% of cases. In 1973, researchers observed a virus particle in the intestinal tissue of children with diarrhea by using electron micrography. The virus shown here was subsequently called rotavirus because of its similarity in appearance to a wheel. Rota is Latin for wheel. The virus is very stable and may remain viable in the environment for weeks or months if not disinfected. Rotavirus is a double-stranded RNA virus of the family Rioviridae. The virus is composed of three concentric shells. The outermost shell contains two important proteins, VP7 or G protein and VP4 or P protein. VP7 and VP4 define the serotype of the virus and induce neutralizing antibody that is probably involved in immune protection. From 1996 through 2005, five strains of rotavirus G1 through G4 and G9 were most prevalent. These five accounted for 90% of the isolates in the United States. The G1 strain alone accounted for more than 75% of isolates. The incubation period for rotavirus diarrhea is very short, usually less than 48 hours. The clinical manifestations of infection vary and depend on whether it is the first infection or reinfection. The first infection after three months of age is generally most likely to cause severe gastroenteritis and dehydration. Infection may be asymptomatic, may cause self-limited watery diarrhea, or may result in severe dehydrating diarrhea with fever and vomiting. Persons who are immunocompromised because of congenital immunodeficiency or because of bone marrow or solid organ transplantation may experience severe or prolonged rotavirus gastroenteritis. Up to one-third of infected children may have a temperature greater than 102 degrees Fahrenheit. The gastrointestinal symptoms generally resolve in three to seven days. Recovery from a first rotavirus infection usually does not lead to permanent immunity. After a single natural infection, 38% of children are protected against any subsequent rotavirus infection, 77% are protected against rotavirus diarrhea, and 87% are protected against severe diarrhea. Reinfection can occur at any age. Subsequent infections produce progressively greater protection and are generally less severe than the first. Recurrent rotavirus infections affect persons of all ages. Recurrent infections are usually asymptomatic or result in mild diarrhea that may be preceded or accompanied by vomiting and low-grade fever. Rotavirus is the most common cause of severe gastroenteritis in infants and young children in the U.S. In the pre-vaccine era, rotavirus infection was nearly universal with more than 80% of children infected by five years of age. Infection can occur at any age, but the most severe disease occurs among children four months to 24 months of age. In the pre-vaccine era, an estimated 3 million rotavirus infections occurred every year in the United States. This was equal to the number of cases of pertussis or measles prior to the availability of vaccines. Rotavirus accounted for more than 400,000 physician visits, 200,000 emergency department visits, and 55 to 70,000 hospitalizations each year among children younger than five years of age. An estimated 20 to 60 children died each year from rotavirus disease. Rotavirus diarrhea resulted in more than 250 million dollars in direct medical costs each year in the U.S., largely due to hospitalization. Total costs, including indirect costs, were more than $1 billion a year. Although rotavirus is usually considered a childhood disease, it also causes gastroenteritis in travelers returning from developing countries, parents and persons caring for children with rotavirus diarrhea, immunocompromised persons, and the elderly. Rotavirus infection of adults is usually asymptomatic but may cause diarrheal illness. The reservoir of rotavirus is the gastrointestinal tract of infected humans. Although rotavirus infection occurs in many non-human mammals, transmission of animal rotaviruses to humans is believed to be rare and probably does not lead to clinical illness. Although immunodeficient persons may shed rotavirus for a prolonged period, a true carrier state has not been described. Rotaviruses are shed in high concentration in the stool of infected persons. Transmission is primarily by fecal oral spread, both through close person-to-person contact and by fomites, such as toys and other environmental surfaces contaminated by stool. In temperate climates, disease is more prevalent during cooler months. Rotavirus is highly communicable, as evidenced by the nearly universal infection of children by age five years in the pre-vaccine era. Factors associated with an increased risk for hospitalization for rotavirus gastroenteritis among U.S. children include lack of breast feeding, child care attendance, and low birth weight, which is probably a proxy for pre-term birth. Other risk factors include the presence of another child younger than 24 months in the household and either having Medicaid insurance or having no medical insurance. Yabbo? Thanks, Andrew. Efforts to produce a vaccine to prevent rotavirus gastroenteritis begin in the 1980s. The first rotavirus vaccines were derived from either bullvine or rhesus monkey origin. Studies demonstrated that these live oral vaccines could prevent rotavirus diarrhea in young children, but efficacy varied widely. The first rotavirus vaccine was licensed in the United States in 1998. This vaccine contained a rhesus parent strain with genes that express an antigen for the predominant serotypes of human rotavirus. This vaccine was taken off the market in 1999 because vaccine recipients had an increased risk of interseception, a type of bowel obstruction, particularly after the first dose. Some research suggested that the risk of interseception increased with increasing age of the first dose. This observation has affected recommendations for the new rotavirus vaccines. There are currently two rotavirus vaccines licensed for use in the United States. Rototech, which we will abbreviate RV-5, is manufactured by Merck. It was licensed by the FDA in February 2006. RV-5 contains five strains of live human bullvine recombinant rotavirus. RV-5 is administered orally in a three-dose series at two, four, and six months of age. The second rotavirus vaccine is Rotorix, which we will abbreviate as RV-1, manufactured by GlaxoSmithKline. RV-1 was licensed by the FDA in April 2008. RV-1 contains one strain of live attenuated human rotavirus. RV-1 is administered orally in a two-dose series at two, and four months of age. Both rotavirus vaccines contain live rotavirus, which is attenuated relative to wild-type rotavirus. Vaccine virus is shed in the stool of infants after receipt of both brands of rotavirus vaccination. Vaccine virus is shed more commonly and for longer periods after RV-1 than after RV-5. However, no data are available on the risk for transmission of vaccine virus to household contacts. Studies to evaluate the safe