 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. Starting 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. Hepatitis B remains a public health problem in the United States even though a safe and effective vaccine has been available since 1981. Hepatitis B vaccine is also one of the most common topics of questions we receive. So we are going to begin this program with a discussion of hepatitis B and address some of the vaccine issues that generate a lot of questions. Hepatitis as a distinct clinical entity has been recognized for 2,500 years. It took another 2,400 years to recognize that there was more than one type and that one of them was transmitted by exposure to human blood or blood products. As a cause of liver disease and cancer, hepatitis B is a disease of enormous global importance. It is caused by hepatitis B virus or HBV. HBV is a small DNA virus very specific to humans. Although the virus is most closely related to viruses which cause hepatitis in wood chucks, ducks, and ground squirrels, humans are the only known host. The virus has never been grown in tissue culture which is why the first vaccine was obtained from chronically infected humans. There are several HBV subtypes that do not affect virulence or infectivity but can be useful in epidemiologic investigations. HBV may retain infectivity for more than 7 days at room temperature. Here is a schematic of HBV. The virus has several antigens but for the purpose of this program, you only need to know about hepatitis B surface antigen. It is shown in this picture as HBSAG. This glycoprotein makes up the outer coat of the virus. Surface antigen itself is not infectious, only the complete virus known as the Dain particle is infectious. But when HBV replicates, it produces surface antigen in huge excess, usually in the form of tubular and spherical structures like you see here. When we find surface antigen in a person's blood, we assume the complete virus is also there and the person is actively infected and capable of transmitting the virus. So surface antigen acts as a marker for active infection. Another thing you need to know about the virus is that antibody to surface antigen indicates immunity to hepatitis B. Other hepatitis B antibodies can be measured but only the presence of hepatitis B surface antibody indicates protection from infection either from previous disease or vaccination. We receive many questions about the interpretation of hepatitis B serologic test. A discussion of this topic is beyond the scope of this program but we have included a table that will help you interpret these tests on the updates and resources web page. It is also in the course text. Hepatitis B is a disease of massive proportion and estimated 2 billion persons worldwide have been infected with HPV and more than 350 million persons have chronic lifelong infection. They are estimated to be more than 1 million chronically infected persons in the United States. Most chronically infected persons are not aware of their infection. The virus is an established cause of chronic hepatitis and cirrhosis and is estimated to be the cause of up to 80% of liver cancer. The World Health Organization estimated HPV was the direct or indirect cause of 600,000 deaths worldwide in 2002. Hepatitis B has a long incubation period 60 to 150 days with an average of 90 days. There may be a nonspecific prodrome of fever, malaise and headache. The clinical illness is not specific for hepatitis B and usually includes anorexia, fatigue, abdominal pain and jaundice. But at least 50% of infections are asymptomatic. Age is the most important factor in whether an infected person has symptoms. Infection in infants is almost always asymptomatic. 5 to 50% of older children and 30 to 50% of adults will develop acute hepatitis following infection with HPV. The most important complication of acute hepatitis B virus infection is fulminant hepatitis, a severe form of acute hepatitis that may lead to acute liver failure. Fulminant hepatitis is estimated to occur in up to 1% of adults with acute hepatitis B virus infection. 10 to 15% of symptomatic infections require hospitalization. The major impact of hepatitis B is not the acute infection. It is the result of chronic infection with the virus. The most common long-term sequelae are cirrhosis and hepatocellular carcinoma. Death can result from either acute fulminant hepatitis or from the chronic disease. This is a Laotian woman with in-stage hepatocellular carcinoma from chronic HPV infection. She was probably infected with the virus by her mother when she was born. The enlarged abdomen is a result of a big liver and ascites or fluid accumulation in the abdominal cavity. In the pre-vaccination era, an estimated 200 to 400 deaths occurred annually from acute fulminant hepatitis. But most of the mortality results from long-term persistent infection with the virus. Every year in the United States, an estimated 3 to 5,000 persons die from HPV-induced liver cancer and cirrhosis. Short of a major breakthrough in the treatment of chronic HPV infection, the number of annual deaths will not change very much anytime soon. This is because it usually takes 20 years or more of chronic infection to result in in-stage liver disease. So even if transmission of hepatitis B virus were completely stopped today, deaths from chronic infection would continue to occur for many years to come. Andrew? Most persons who die from hepatitis B are chronically infected and have virus in their blood and body fluids continuously. Most persons who become chronically infected will remain infected the rest of their lives. The overall risk of becoming chronically infected is 5 to 10 percent and may result from either symptomatic or asymptomatic illness. There are estimated to be about 1.2 million persons chronically infected with HPV in the U.S. now. Several thousand newly infected persons become chronically infected every year. Although the immunologic mechanism of chronic infection is not well understood, risk factors for becoming chronically infected have been identified. The most important risk factor is the age of the person when the infection occurs. The earlier in life infection occurs, the higher the risk of becoming chronically infected. This graph shows the percent of infected persons who become chronically infected on the vertical axis by the age of infection along the horizontal axis. Up to 90 percent of infants infected at birth will become chronically infected. 50 percent of infections at one year of age will become chronic. By about five years of age, the risk of becoming chronically infected approaches the adult risk of about 5 percent. Infection early in life is very dangerous because it frequently leads to chronic infection. Chronic liver disease develops in two-thirds of persons with chronic HPV infection and 15 to 25 percent will die prematurely from cirrhosis or liver cancer. Early infected persons also remain a source for transmission of virus for others. This is why the reduction of perinatal transmission has been one of the priorities of the U.S. Hepatitis B control program. Our knowledge of the epidemiology of HBV has driven the vaccination recommendations since the vaccine was first licensed in 1981. Hepatitis B is a human disease and the reservoir is humans with acute or chronic infection. It is blood-borne, that is, transmission results from contact with infected blood or body fluids derived from blood. In practice, the only body fluids likely to transmit HBV are blood, vaginal secretions, semen, and maybe saliva on very rare occasions. A human bite has been implicated in transmission. Persons with asymptomatic infections transmit the virus just the same as symptomatic persons. The virus is communicable one to two months before and after onset. This graph shows the number of reported cases of Hepatitis B by year since 1978. The first Hepatitis B vaccine was licensed in 1981. You might expect a decline in incidence after the vaccine was licensed, but the number of reported cases continued to rise. It peaked in 1985, then slowly declined. It is believed that the decline was not due to vaccine but to HIV-AIDS education that led to behavioral changes among men who have sex with men and later among IV drug users. The rate of Hepatitis B has declined 80 percent since 1990 due in large part to the implementation of universal childhood immunization. Since 2000, an average of about 7,600 cases of Hepatitis B infection have been reported each year, but these reported cases only represent a fraction of the actual incidence. It is estimated that in the pre-vaccine era, 300,000 persons were infected annually with Hepatitis B virus, including about 24,000 infants and children. Because of vaccination and risk reduction behaviors in high-risk groups, the number of persons infected in the United States declined to an estimated 51,000 in 2005. In the United States in 2005, the highest incidence of acute Hepatitis B was among adults 25 to 45 years of age. Approximately 79 percent of newly acquired infections are associated with high-risk sexual activity or injection drug use. Other known exposures, such as household and occupational exposures, together account for 5 percent of new infections. 16 percent deny a specific risk factor for infection. In 1990, healthcare personnel accounted for 2 percent of HBV infections, 2 or 3,000 new infections each year. Since that time, the rate of infection among healthcare personnel has declined by 95 percent and is now lower than the rate for the general population. Hepatitis B vaccine has made occupational HBV infection a thing of the past. So the message from all this is that Hepatitis B vaccine has led to a big decline in groups with high vaccination levels, children and healthcare personnel, but thousands of cases are still occurring, mainly among young adults. Reducing the disease burden in this group requires creative vaccination programs to reach high-risk adults, particularly in clinics that treat sexually transmitted diseases and injection drug use. Bill? The first Hepatitis B vaccine was licensed in the United States in 1981. The Hepatitis B surface antigen for the vaccine was purified from the blood of chronically infected humans. In 1986, the first genetically engineered or recombinant Hepatitis B vaccine was licensed. The plasma-derived vaccine was taken off the market in 1992. There are now three combination vaccines that contain Hepatitis B that we'll discuss a little later. All Hepatitis B vaccines are composed of recombinant Hepatitis B surface antigen. The antigen is produced in genetically engineered yeast cells. The yeast cells contain the part of the Hepatitis B gene that codes for surface antigen. The vaccine does not contain any other part of the Hepatitis B virus. The routine Hepatitis B vaccine schedule is three doses. Vaccine efficacy after a full series is estimated at 95 percent with a range of 80 to 100 percent. The duration of immunity is long 15 years or more. Routine booster doses are not recommended. Hepatitis B vaccine can and should be administered simultaneously with all other vaccines in both children and adults. It should be administered intramuscularly either in the anterolateral thigh of an infant or the deltoid of an older child or adult. The Hepatitis B vaccines available in the U.S. are produced by two different manufacturers, Merck and GlaxoSmithKline. Both companies produce both pediatric and adult formulations. RecombaVaxHB from Merck is available in three formulations. A pediatric formulation that contains five micrograms per half milliliter dose. An adult formulation with 10 micrograms per milliliter. And a dialysis formulation with 40 micrograms per milliliter. NJRXB from GlaxoSmithKline is available in two formulations. A pediatric formulation with 10 micrograms per half milliliter dose. And an adult formulation that contains 20 micrograms per milliliter. Both formulations are available without thimerosal as a preservative. This graphic shows the recommended dose of Hepatitis B vaccine by age group and vaccine brand. All infants and children younger than 11 years of age, shown in the first row, receive a half milliliter dose of either RecombaVax or NJRX. Although the amount of antigen in the half milliliter dose differs by manufacturer, the vaccines are considered equivalent and are completely interchangeable. Adolescents 11 to 19 years of age in the second row should also receive a half milliliter dose of either RecombaVax or the pediatric formulation of NJRX. Adults 20 years and older should receive one milliliter of either RecombaVax or the adult formulation of NJRX. As with the pediatric formulations, the adult formulation of NJRX has twice as much antigen per dose as RecombaVax, but the vaccines are considered to be equivalent and are interchangeable. An adult who receives one or two doses of adult RecombaVax can complete the series with a dose of NJRX or vice versa. Don't be misled by the higher antigen content of NJRX. The fact that it has twice the antigen per dose does not mean that it's a better vaccine or that you can give a half dose if you should substitute NJRX for RecombaVax. Children and adolescents 19 years and younger should always receive a half milliliter dose and adults 20 years and older should always receive a one milliliter dose regardless of which vaccine you are using. We get a lot of questions about waning immunity to hepatitis B vaccine and the need for booster doses. It is true that antibody level may decline after vaccination. In fact, up to 50 percent of recipients may lose detectable antibody by 15 years after vaccination, but the level of antibody is only part of the issue. Persons who respond to the vaccine develop immunologic memory following vaccination. This means that B lymphocytes have been produced that are primed to produce more hepatitis B surface antibody the next time hepatitis B surface antigen is encountered. We know that this immunologic memory lasts for many years after successful vaccination. Antibody may drop to a low level, but an anemnestic or memory response occurs upon exposure to HPV and antibody levels increase very quickly. Since the incubation period of HPV is so long, the immune system can mount a protective response before the virus can do any damage. A symptomatic HPV infection has been occasionally documented in persons who responded to the vaccine, but chronic infection has rarely been documented among vaccine responders. Since chronic infection leads to severe sequela and is responsible for most of the mortality, it's what we most want to prevent. Booster doses of hepatitis B vaccine are not routinely recommended for any group because there's no evidence that they're necessary for continued protection. Routine periodic serologic testing to assess the immune status of vaccinated persons is also not recommended except for persons on dialysis and possibly for other immunocompromised persons. The duration of hepatitis B immunity following vaccination will continue to be studied for years to come, particularly among those vaccinated as infants. If breakthrough infections, particularly chronic infections, begin to appear 10, 20, or 30 years from now, booster doses may be needed, but not now. Donna. The hepatitis B vaccination strategy has evolved since the vaccine was licensed in 1981. When new recommendations were made, they did not replace the prior recommendations. The recommendations were cumulative, so now hepatitis B vaccine is recommended for persons of many ages. Hepatitis B vaccine should be administered to all infants without contraindications beginning at birth. All adolescents through 18 years of age should receive hepatitis B vaccine if they have not already received it. The routine medical visit at 11 or 12 years is a good opportunity to be sure adolescents have been vaccinated. The vaccine should also be offered to adults at increased risk of HBV infection. An ACIP statement that specifically addresses hepatitis B vaccination of adults was published in December 2006. In it, ACIP recommends universal hepatitis B vaccination for all unvaccinated adults in settings in which a high proportion of adults have risk for HBV infection. This would include settings such as sexually transmitted disease and HIV testing and treatment facilities, drug abuse treatment and prevention settings, and correctional facilities. In other primary care and specialty medical settings in which adults at risk for HBV infection receive care, all patients should be provided information about the disease and benefits of vaccination. The vaccine should be available in these settings. We will include a link to this important document on our updates and resources webpage. The vaccination schedules are very similar for all age groups. The childhood hepatitis B vaccination schedule recommended by the ACIP and the American Academies of Pediatrics and Family Physicians begins at birth. The second dose is given at one to two months of age and the third dose at six to 18 months of age. Note the minimum intervals four weeks between doses one and two and eight weeks between doses two and three. Do not give the vaccine at intervals shorter than these minimums. The third dose has three intervals and age rules that you should follow. The third dose should be given a minimum of eight weeks after the second dose and at least 16 weeks after the first dose. These two rules apply to anyone of any age receiving the vaccine. For infants there is one more rule. The infant should be at least 24 weeks of age before receiving the third dose. The reason for these three rules is the desire to maximize the response to the vaccine. There are limited data on schedules other than these. If a dose of hepatitis B vaccine is given at an interval or age less than these minimums, the dose should not be counted. The four-day grace period can be applied to these intervals if your state accepts it. But what about doses that are separated by longer than the recommended interval? As with all vaccines routinely used in the U.S., it is not necessary to restart the series or add additional doses if the interval between doses is prolonged. Just continue the series where it was interrupted. Preterm infants with a very low birth weight present a challenge. Infants who weigh less than 2,000 grams have a decreased response to hepatitis B vaccine. As a result, the first dose of vaccine should be delayed until the child is one month old if the mother is documented to be hepatitis B surface antigen negative. At one month of age, these infants respond as well as infants of normal birth weight. But this applies only to routine hepatitis B vaccination. Post-exposure management must be started immediately if the mother is hepatitis B surface antigen positive or if the mother's surface antigen status is not known regardless of the child's weight. Post-exposure management includes both vaccine and hepatitis B immune globulin or HBIG. There is one other unique aspect of vaccination of preterm infants who weigh less than 2,000 grams. If the infant's mother is surface antigen positive or her status is not known, you should give a dose of hepatitis B vaccine at birth along with HBIG. But this first dose should not be counted. The infant should receive three additional doses beginning when the infant reaches one month of age. Andrew? There are now three combination vaccines that contain hepatitis B. Comvax, pediurex, and twinrix. Comvax and pediurex are approved only for children. Twinrix is approved only for adults 18 years of age and older. Comvax is a combination hepatitis B Hib vaccine produced by Merck and was licensed in 1996. Comvax contains a standard five microgram dose of Merck's pediatric hepatitis B vaccine and a standard dose of Merck's Hib vaccine, Pedvax Hib. Comvax does not contain thimerosal as a preservative. As with other combinations, the vaccine can be used when either component is indicated and neither antigen is contraindicated. Hib vaccine should not be given to infants younger than six weeks of age, so Comvax cannot be administered to infants younger than six weeks of age. Although not approved by FDA for this use, Comvax may be used if the infant's mother is known to be surface antigen positive or not known. ACIP approved this off-label use of Comvax in 1997. These infants must receive a birth dose of monovalent hepatitis B vaccine and the hepatitis B series can be completed with Comvax beginning at six to eight weeks of age. In 2002, the Food and Drug Administration licensed a new combination vaccine, Pedirix, which is manufactured by GlaxoSmithKline. The vaccine contains DTAP, inactivated polio, and hepatitis B vaccines. The DTAP component is Infinrix and the hepatitis B component is Endurix B, which were previously licensed in the U.S. Pedirix is approved for the first three doses of the DTAP and IPV series, which are usually given at about two, four, and six months of age. It is not approved for the booster doses of DTAP or IPV. However, Pedirix is approved for use through six years of age. The minimum age for the first dose of Pedirix is six weeks, so it cannot be used for the birth dose of the hepatitis B series. Pedirix may be used in infants born to women who are hepatitis B surface antigen positive or whose hepatitis B status is not known. Like Comvax, Pedirix is not approved by FDA for this use. But in 2003, ACIP approved the off-label use of Pedirix to complete the hepatitis B series for these infants. But remember that the minimum age for Pedirix is six weeks, so it must not be used for the birth or one month dose of the hepatitis B series. I would like to remind you of the combination vaccine interval rule. It is that the minimum intervals between doses of a combination vaccine are dictated by the single antigen with the longest minimum intervals. So for Pedirix, the minimum intervals are determined by the hepatitis B component. As for hepatitis B vaccine, the minimum interval between the first two doses of Pedirix is four weeks. The third dose must be administered at least eight weeks after the second dose and should follow the first dose by at least 16 weeks. To be counted as a valid final dose of hepatitis B vaccine, the third dose should not be administered before 24 weeks of age. One more point about combination vaccines that contain hepatitis B vaccine. All infants should receive a dose of hepatitis B vaccine shortly after birth. Either convex or Pedirix can be used to complete the hepatitis B schedule for children that receive a birth dose. This means the child will receive four doses of hepatitis B vaccine. This is not a problem. It is not necessary to switch back and forth between a combination and single antigen hepatitis B vaccine just to avoid giving four doses. Just go ahead and use the combination vaccine as usual even though this will result in one extra dose of hepatitis B vaccine for the child. The third combination vaccine that contains hepatitis B vaccine is Twinrix. Twinrix is produced by GlaxoSmithKline and was licensed by FDA in 2001. It contains a standard adult dose of GSK's hepatitis B vaccine, Enderix, and a pediatric dose of their hepatitis A vaccine, Havrex. The standard schedule is a three-dose series at 0, 1, and 6 to 12 months. Twinrix is approved only for adults 18 years of age and older. A pediatric version of Twinrix is not available in the United States. Since Twinrix contains a standard adult dose of hepatitis B vaccine, it can be used interchangeably in a schedule with monovalent hepatitis B vaccine. We will discuss an alternate Twinrix schedule and schedules that include both Twinrix and monovalent hepatitis A in the hepatitis A segment of the program. All children and adolescents through age 18 years should receive hepatitis B vaccine. Adults at increased risk of HBV infection should also be vaccinated. The routine adolescent and adult schedule is three doses. For the usual schedule, the first two doses should be separated by at least one month, and the third dose is usually given five months after the second. If an accelerated schedule is required, the minimum interval between the second and third doses is eight weeks. The first dose should always be separated from the third dose by at least 16 weeks. Adolescents should receive one-half milliliter of pediatric formulation. Adults 20 years and older should receive one milliliter of adult formulation. In 1999, Merck received FDA approval for an alternative hepatitis B vaccination schedule for adolescents. This alternative schedule is for two adult doses, 10 micrograms of recombinant HB separated by four to six months. Seroconversion rates, post-vaccination antibody titers, and adverse reactions were similar using this schedule and the standard schedule of three five microgram doses of recombinant HB. This alternative schedule may only be used for adolescents 11 through 15 years of age, and the schedule only applies to the Merck hepatitis B vaccine. I want to repeat this. If you decide to use this two-dose schedule for adolescents in your practice, it must not be started before age 11 and should be completed by the 16th birthday. If the child has already received one or more five microgram pediatric doses, he or she should complete the regular three-dose series and not be switched to the two-dose series. Also, Enderx B is not approved for this schedule. In this situation, the two vaccines are not interchangeable. One final note on the two-dose adolescent schedule. If you decide to use it, please document clearly on the vaccination record, both yours and the personal record, that you gave an adult dose. If you just record hepatitis B vaccine without noting the dose, someone reviewing the record will assume appropriately that it was a standard pediatric dose. Immunization nurses have many talents, but clairvoyance is usually not one of them. Document the doses you administer clearly and do not make anyone guess. Bill. We receive many questions about serologic testing after vaccination. In most circumstances, it is not necessary. Post-vaccination serologic testing is not routinely recommended after routine vaccination of infants, children, adolescents, or most adults. But there are situations where it is recommended. These include infants born to hepatitis B surface antigen-positive women, either acutely or chronically infected, hemodialysis patients, immunodeficient persons, sex partners of persons with chronic HBV infection, and certain healthcare personnel. Since 1997, the ACIP has recommended that healthcare personnel who have contact with patients or blood and are at ongoing risk for injury with sharp instruments or needles should be tested for antibody after vaccination. Routine testing is not recommended for persons at low risk of exposure, such as public safety workers and healthcare personnel without direct patient contact. Testing for antibody to hepatitis B surface antigen should be done one to two months after the third dose of vaccine. But what about the thousands of healthcare personnel who were vaccinated before the 1997 recommendations were published? ACIP does not recommend catch-up serologic testing programs. These persons can be tested as necessary if they are exposed. All healthcare personnel who may be exposed to blood or sharp injury should have written documentation of having received a three-dose series of hepatitis B vaccine. Healthcare personnel who cannot provide this documentation should be vaccinated. This recommendation includes personnel without documented vaccination who test positive for hepatitis B surface antibody. Post-vaccination serologic testing will occasionally reveal someone who failed to respond to a series of three doses that were administered in the correct dosage and route. Persons who do not respond to the first series of three doses should complete a second series of three doses or be evaluated to determine if they are already chronically infected. Persons who do not respond to the initial three-dose series have a 30 to 50 percent chance of responding to a second three-dose series. The second series should be given on the usual schedule of zero, one and six months but an accelerated schedule of zero, one and four months can also be used. Revaccinated persons should be retested for an antibody response one to two months after completing the second series. If you test enough people you will eventually encounter someone who fails to respond to six doses of hepatitis B vaccine. You need to evaluate the person for chronic HPV infection if this has not already been done. ACIP does not recommend more than six total doses of hepatitis B vaccine for otherwise healthy persons. Those who fail to respond to six doses and are not surface antigen positive should be assumed to be susceptible and be given post-exposure prophylaxis with hepatitis B immune globulin if a high-risk exposure occurs. The most recent recommendations for post-exposure prophylaxis after occupational exposure to HPV were published in 2001. A table in this document can help you determine when HBIG is needed. There's a link to the document on the updates and resources webpage. Hepatitis B vaccine has few true contraindications and precautions. The only contraindication is a severe allergic reaction to a vaccine component or following a prior dose. Moderate or severe acute illness is a precaution and vaccination should be deferred until the acute illness improves. Hepatitis B vaccine is inactivated and the adverse reactions following it are similar to those following other inactivated vaccines. Pain at the injection site is reported in 13 to 29 percent of recipients. Mild systemic complaints such as fatigue or headache are reported in 11 to 17 percent of adults. A temperature of 100 degrees Fahrenheit or higher occurs only in about 1 percent of recipients. Transmission of hepatitis B virus in the perinatal period is extremely dangerous because it leads to chronic infection for up to 90 percent of infected infants. All pregnant women should be tested at least once for hepatitis B surface antigen status during each pregnancy. Women who are not screened during early pregnancy or who engage in behaviors that put them at high risk for infection such as injection drug use should be tested at the time of admission to the hospital for delivery. Infants born to women who are hepatitis B surface antigen positive must receive post-exposure prophylaxis immediately after birth. The basic recommendations for perinatal management are summarized on this next graphic. For a newborn whose mother is acutely or chronically infected with HBV begin treatment within 12 hours of birth. In the first 12 hours give hepatitis B vaccine and HB at different sites for example each thigh. For infants weighing at least 2,000 grams at birth give or ensure that someone gives the second dose at one to two months of age and complete the series by six months of age. An infant who weighs less than 2,000 grams at birth and whose mother is hepatitis B surface antigen positive should get a total of four doses of vaccine to complete the series. Test the child for anti-HBS and hepatitis B surface antigen after completion of at least three doses of hepatitis B vaccine at nine to 18 months of age that is about three months after the final dose of the vaccination series. Prevention of perinatal and early childhood infection by providing hepatitis B vaccine to newborns is a critical element of our hepatitis B prevention strategy. More details about implementation of the birth dose and prevention of perinatal HBV transmission can be found in part one of the hepatitis B ACIP statement published in December 2005. The document also includes information on management of women found to be surface antigen positive, hepatitis B post-exposure prophylaxis and much more. We will have a link to these recommendations on our updates and resources webpage. Outbreaks of jaundice which were probably hepatitis A were reported in the 17th and 18th centuries often associated with military campaigns. Hepatitis A was originally called infectious hepatitis and was differentiated epidemiologically from long incubation period hepatitis B in the 1940s. The development of serologic test in the 1970s helped differentiate hepatitis A from other types of non-B hepatitis. Hepatitis A virus was first isolated in 1979 and a vaccine was first licensed in 1995. Hepatitis A virus or HAV is a pocorna virus with an RNA genome. Humans are the only natural host although some non-human primates can be infected in laboratory conditions. Depending on conditions HAV can survive in the environment for months. The virus is relatively stable at low pH levels and moderate temperatures but can be inactivated by high temperature above 185 degrees Fahrenheit, formalin and chlorine. HAV infection is acquired by mouth and the virus replicates in the liver. After 10 to 12 days virus is present in blood and in the feces. A large amount of virus is shed in the stool of an infected person. The incubation period of hepatitis A is 15 to 50 days with an average of about 28 days. Symptomatic illness is not specific for hepatitis A and is indistinguishable from other types of acute viral hepatitis. Hepatitis A typically has an abrupt onset of fever, malaise, anorexia, nausea, abdominal discomfort, dark urine and jaundice. Clinical illness usually lasts less than two months but 10 to 15 percent of infected persons have prolonged or relapsing signs and symptoms for up to six months. The likelihood of symptomatic illness from HAV infection is directly related to age. Children younger than six years of age are generally asymptomatic. Older children and adults usually have symptoms with jaundice occurring in more than 70 percent of patients. Unlike hepatitis B virus infection with hepatitis A virus does not lead to chronic infection. So complications of hepatitis A are related to the acute disease. 10 to 20 percent of persons with symptomatic hepatitis A require hospitalization. The overall case fatality rate is about 0.3 percent or about one in 330 reported cases. But the fatality rate may be as high as 2 percent among persons 40 years of age and older. Death is caused by fulminate hepatitis and liver failure. Adults with hepatitis A lose an average of 27 work days per illness. Health departments incur the cost of post-exposure prophylaxis for 11 contacts per case. In 1989 the estimated annual cost of hepatitis A in the United States was more than 200 million dollars. Andrew. The epidemiology of hepatitis A is changing in the United States. In some populations it has changed a lot and we think these changes are because of the vaccine. Hepatitis A is endemic throughout the world. Humans with acute hepatitis A virus infection are the only reservoir. Chronic infection does not occur as it does for hepatitis B virus infection. Hepatitis A is transmitted by the fecal oral route either by direct person-to-person contact or ingestion of contaminated food or water. The virus is shed in the stool and is communicable two weeks before the onset of illness until a week after the onset of jaundice. The risk for transmission of hepatitis A virus depends on host and environmental factors and varies in different settings. For example without post-exposure prophylaxis secondary attack rates of 15% to 30% have been reported in households with higher rates of transmission occurring from infected young children than from infected adolescents and adults. In contrast attack rates are low among patrons of food service establishments who have been exposed to food handlers with hepatitis A virus infection. Most infected food handlers do not transmit hepatitis A virus to exposed consumers or restaurant patrons. This graph shows the source of infection of reported hepatitis A cases in the U.S. from 1990 through 2000. The most frequently reported source of hepatitis A virus infection in the U.S. is sexual or household contact with the person with hepatitis A accounting for about 14% of reported cases. Men who have sex with men shown here as MSM account for about 10%. Childcare attendance or employment or contact with the child in child care accounts for about 8% of cases. About 6% of cases had a history of injection drug use and 5% had a history of recent international travel. The source of infection for almost half of persons with hepatitis A is unknown. Groups at increased risk of hepatitis A include international travelers, men who have sex with men and users of illegal drugs. Outbreaks of hepatitis A have also been reported among persons working with non-human primates. This is the only occupational group known to be at increased risk of hepatitis A. This graph shows reported cases of hepatitis A by year since 1966 when it became nationally reportable as a distinct entity. Reported cases peaked in 1971 with more than 59,000 cases. Notice the cyclic increases in cases about every 10 years. The last peak occurred in 1995 but the incidence of hepatitis A is high even between the peaks. An average of 27,000 cases were reported annually in the United States during the 1990s with 23,000 cases reported in 1998. It is estimated that for every reported case there are five to six unreported cases. That means that more than 100,000 hepatitis A infections occurred in the United States each year during the 1990s. The number of reported cases has fallen since 1998 with about 5,900 cases reported in 2004. The highest rates of reported hepatitis A are in older children and young adults. The incidence of reported hepatitis A in children younger than five years is substantially less than older children. But cases in this age group are grossly underreported because most infections in young children are not symptomatic. Historically, most cases of hepatitis A occurred as part of community-wide outbreaks with the majority of infections occurring among children and their adult contacts. In the pre-vaccine era, much of the disease reported in the U.S. was occurring in the western regions of the country. Cases reported by 17 predominantly western and southwestern states accounted for more than two-thirds of all cases reported in the pre-vaccine era. However, these states represented less than one-third of the U.S. population. Based on this information, in 1999, ACIP recommended that children living in the 11 states which historically had the highest rates of hepatitis A be routinely vaccinated against the disease. Those 11 states are shown here in green. It was also suggested that vaccination be considered for children in an additional six states shown in yellow. Rates in these six states were not as high as those in the 11 highest incidence states but were still consistently higher than the national average. Since those recommendations were made, we have seen a dramatic change in the epidemiology of hepatitis A in the United States. This graph shows the overall rate of hepatitis A in the United States from 1990 through 2004. It shows the decline in rate that began in 1995 and accelerated in 1999. The year routine childhood vaccination was recommended in the high incidence areas. The rate has declined by 76 percent relative to the average rate seen in the pre-vaccine years of 1990 through 1997. The 2004 rate of 1.9 per 100,000 population is the lowest ever recorded. The decline has been greatest in these 17 states where routine vaccination of children is recommended or suggested, shown here by the blue line. The rate of hepatitis A in the rest of the country is shown as the gold line. For the first time rates are similar across all regions of the country. The 1999 hepatitis A ACIP statement targeted children in the highest incidence states. Children historically have had the highest rates of disease. Since that time rates among children have declined more than rates among adults. Now also for the first time rates are similar across all age groups. Hepatitis A rates now are significantly lower than any previously recorded. In addition the decline has been greater in the age groups and geographic locations recommended for routine vaccination. Together these factors indicate that the strategy of routine childhood vaccination in areas with increased risk of infection has played a significant role in reducing overall rates of hepatitis A in the U.S. Based on these data the ACIP voted in 2005 to extend the benefits of hepatitis A vaccination to all areas of the country by recommending routine hepatitis A vaccination for all children. Bill. Hepatitis A vaccine was first licensed in the United States in 1995. Two hepatitis A vaccines are now available. Both vaccines are inactivated whole virus vaccines. Havricks is GlaxoSmithKline's vaccine. VACTA is produced by Merck. The vaccines are considered equivalent and interchangeable. Both are given as a single dose with a booster dose six to 18 months after the first dose. Both vaccines are available in pediatric and adult formulations. The pediatric formulations of both vaccines are for persons 12 months through 18 years. The adult formulations are for persons 19 years and older. The pediatric and adult formulations of both vaccines are supplied as liquid vaccine in pre-filled syringes and single dose vials. Both manufacturers pre-filled syringe and the VACTA single dose vial contain dry natural latex rubber. Neither vaccine contains thimerosal as a preservative. Hepatitis A vaccines are highly immunogenic and large trials have produced estimates of 94 to 100 percent protection against clinical hepatitis. In clinical trials 95 percent of adults are seropositive for hepatitis A antibody within a month following one dose and 100 percent are seropositive after two doses. The vaccines are just as impressive in children 12 months and older and in adolescents with more than 97 percent seropositive after one dose and 100 percent seropositive after two doses. For both vaccines the schedule is one dose with a second or booster dose at least six months after the first dose. The booster dose should be based on the person's age at the time of the booster, not the age when the first dose was given. For example, if a child received the first dose of the pediatric formulation of VACTA at 18 years of age and returns for the booster dose at age 19 years the booster dose should be the adult formulation, not the pediatric formulation. The minimum interval between the first and booster doses of hepatitis A vaccine is six calendar months. If the interval between the first and booster doses of hepatitis A vaccine is longer than the recommended interval of six to 18 months, it is not necessary to repeat the first dose. Since the vaccines were first licensed the strategy has been to identify and vaccinate two groups of persons. The first are persons at high risk for hepatitis A virus infection. The second is persons at high risk for severe sequela of hepatitis A virus infection. Targeted vaccination undoubtedly prevented some cases of hepatitis A, but this strategy did not have a significant impact on the burden of disease in the U.S. In 1999 ACIP recommended that states with a high incidence of hepatitis A incorporate hepatitis A vaccine into their routine childhood vaccination programs. This strategy has contributed to a dramatic decline in the hepatitis A incidence in these areas. The next logical step in hepatitis A prevention in the U.S. is routine vaccination of all children. These recommendations were published in May 2006. The ACIP recommends that all children should receive hepatitis A vaccine at 12 through 23 months of age. Vaccination should be integrated into the routine childhood vaccination schedule. Children who are not vaccinated by two years of age can be vaccinated at subsequent visits. Some areas in the U.S already have an existing hepatitis A vaccination program for children two through 18 years of age. These programs should be maintained. New efforts focused on routine vaccination of children 12 months of age should not should enhance not replace ongoing vaccination programs for older children. In areas without an existing hepatitis A vaccination program catch up vaccination of unvaccinated children two through 18 years of age can be considered. The ACIP does not recommend a routine catch up vaccination program for older children. However, such programs might be warranted in the context of say rising incidents or ongoing outbreaks among children or adolescents. Andrew. ACIP continues to recommend hepatitis A vaccination for groups at increased risk of HAV infection. The traditional high-risk groups targeted for hepatitis A vaccination include international travelers, men who have sex with men, drug users, both injecting and non-injection, and persons with occupational risk. This group is limited to certain laboratory workers and animal handlers. It does not include healthcare personnel, emergency or first response personnel, or persons with occupational exposure to sewage. Vaccination is also recommended for persons with chronic liver disease. Persons with chronic liver disease are not necessarily at increased risk of HAV infection but are at increased risk of complications of hepatitis A. Hepatitis A vaccination is recommended for persons 12 months of age and older traveling to countries with high or intermediate risk of hepatitis A virus infection. These areas include basically the entire world except Canada, Western Europe, Scandinavia, Japan, New Zealand and Australia. Historically, international travelers often received immune globulin for passive protection against hepatitis A virus infection. In the past, the ACIP recommended that for optimal protection, persons traveling to an area where the risk for transmission was high less than four weeks after the first dose of vaccine could also receive immune globulin. In October 2007, the ACIP published revised recommendations for the use of hepatitis A vaccine and IG among international travelers. The first dose of hepatitis A vaccine should be administered as soon as travel is considered. For healthy persons 40 years of age or younger, one dose of single antigen vaccine administered at any time before departure can provide adequate protection. Adults older than 40 years immunocompromised persons and persons with chronic liver disease are at increased risk of severe hepatitis A. Prevention of hepatitis A virus infection in these groups is vital. Persons at risk of severe disease from hepatitis A virus planning to travel in two weeks or sooner should receive the first dose of vaccine and also simultaneously can be administered immune globulin. Vaccine and IG should be administered with separate syringes at different anatomic sites. Hepatitis A vaccine is not approved for children younger than 12 months of age, so these children should continue to receive immune globulin prior to travel to a high risk area. In the same October 2007 publication, the ACIP also revised its recommendations for hepatitis A post-exposure prophylaxis. In the past, only immune globulin has been recommended for post-exposure prophylaxis. Based on new data comparing IG and hepatitis A vaccine, the ACIP now recommends that vaccine can be used without IG for some persons. For healthy persons aged 12 months through 40 years of age, single antigen hepatitis A vaccine at the age appropriate dose should be administered as soon as possible after exposure. Vaccine is preferred to IG because of vaccine advantages that include long-term protection and ease of administration. For persons older than 40 years immune globulin is preferred because of the absence of information regarding vaccine performance and the more severe manifestations of hepatitis A in this age group. Vaccine can be used if IG cannot be obtained. Immune globulin should be used for children younger than 12 months of age, immunocompromised persons, persons with chronic liver disease, and persons for whom vaccine is contraindicated. More details on these recommendations are in the October 19th, 2007 edition of Morbidity and Mortality Weekly Report. Bill? Hepatitis A vaccine is also available in a combination vaccine. Twin Rix is produced by GlaxoSmithKline and was licensed by FDA in 2001. It contains a standard adult dose of GSK's hepatitis B vaccine Injurix and a pediatric dose of their hepatitis A vaccine Haverix. The vaccine is administered in a three-dose series at 0, 1, and 6 to 12 months. Twin Rix is approved only for adults 18 years of age and older. No pediatric version of Twin Rix is available in the United States. In 2007, the Food and Drug Administration approved a new schedule for Twin Rix. We have received many questions about this new schedule. Although the company refers to it as an accelerated schedule because of the timing of the first three doses, it actually requires a year to complete and requires four total doses. The new schedule is doses at 0, 7, and 21 to 30 days and a booster dose at 12 months. Like the standard Twin Rix schedule, the new schedule is only approved for persons 18 years and older. Based on immunogenicity data submitted to the FDA and in the medical literature, the first three doses of the newly licensed Twin Rix schedule provide equivalent protection to the first dose in the standard single antigen adult hepatitis A vaccine series and the first two doses in the standard adult hepatitis B vaccine series. ACIP has not yet made a recommendation for the use of this new schedule. It's our opinion that the standard schedule of either Twin Rix or single antigen vaccines should be used whenever possible for two reasons. The first is cost. Three doses of Twin Rix on the standard schedule are less expensive than four doses required for the new schedule. The second is because of the time required to complete the series. Six months for the standard schedule and 12 months for the new schedule. The newly licensed schedule may be useful when travel or other potential exposure is imminent that is in less than a month. In this situation the second dose of hepatitis B vaccine or Twin Rix cannot be administered according to the standard schedule one to two months after the first dose. There is no apparent increased benefit of the newly licensed schedule for the hepatitis A vaccine component. Serial conversion is nearly 100% after either three doses of Twin Rix or a single dose of single antigen adult hepatitis A vaccine. There's also no apparent increased benefit of the accelerated schedule for the hepatitis B component compared to administration of two hepatitis B vaccine doses one to two months apart. In addition, both hepatitis A vaccine and the hepatitis B vaccine series are known to be effective when the series are begun at the time of exposure. We have no data on how to manage a person who starts on the newly licensed schedule and then has a lapse in the schedule. But it would seem reasonable that if exposure was still imminent just to continue the series where it was interrupted. But if the lapse occurs after the first dose of the new schedule and the second dose can be administered according to the standard schedule one to two months after the first dose we suggest reverting to the standard schedule of either Twin Rix or single antigen vaccine. We also receive many questions about the use of Twin Rix and single antigen hepatitis A vaccine in the same series. Schedules using both vaccines have not been studied but here are some general principles that can be applied to the situation. Adult formula single antigen hepatitis A vaccine may be used to complete a schedule begun with Twin Rix and vice versa. However, interchanging the vaccines will still require a total of three doses. Schedules that include two doses of Twin Rix can be completed with one dose of adult formulation hepatitis A vaccine. Schedules that include one dose of Twin Rix must include two doses of adult formulation hepatitis A vaccine. The hepatitis A component of Twin Rix is not counted in this situation since it's equivalent to half an adult dose. If you substitute hepatitis A vaccine for Twin Rix you should maintain the spacing recommended for Twin Rix one month between doses one and two and five months between doses two and three. If protection from hepatitis A is needed in a month then you should consider using single antigen hepatitis A vaccine rather than Twin Rix. The serial conversion rate one month after a single dose of single antigen vaccine is about 98 percent. Serial conversion a month after a single dose of Twin Rix is about 90 percent. Hepatitis A vaccine should not be administered to persons with a history of a severe allergic reaction to a vaccine component or following a prior dose. Vaccination of persons with moderate or severe acute illness should be deferred until the illness improves. The safety of hepatitis A vaccine during pregnancy has not been determined. However because it is an inactivated vaccine the theoretical risk to the fetus is low. The risk associated with vaccination should be weighed against the risk for HAV infection. Because hepatitis A vaccine is inactivated no special precautions are needed when vaccinating immunocompromised persons. For both hepatitis A vaccines the most frequently reported adverse reaction following vaccination is a local reaction at the site of injection. Injection site pain, erythema or swelling is reported in 20 to 50 percent of recipients. These symptoms are generally mild and self limited. Mild systemic reactions such as malaise, fatigue and low grade fever are not common and are reported in fewer than 10 percent of recipients. No serious adverse reactions have been reported. Routine hepatitis A vaccination of children is preventing a substantial number of HAV infections. Vaccination of children also eliminates a major source of infection for other children and adults, the group that tends to get more severe disease. Eventually this strategy will prevent infection in adults who are vaccinated as children because immunity appears to persist for many years. We would like to present a case study that addresses issues that we have discussed on the program today. The case studies are available on the updates and resources webpage for this program. Maria is a two-year-old who has been hospitalized for four weeks following a motor vehicle crash. Because of injuries to her pelvis she is in a cast from her waist to her knees. She is otherwise healthy. Maria is doing well and will be discharged tomorrow. It is currently influenza season and there is an outbreak in the community affecting the hospital. Maria's mother is pregnant. Maria's grandmother who lives with the family is receiving chemotherapy for multiple myeloma. The hospital is able to access Maria's immunization history through the state registry. Her record indicates that she had hepatitis b vaccine at birth. Pediatrics, the DTAP-IPV hepatitis b combination vaccine at two four and six months of age, she received a full series of hip vaccine at two four six and 12 months of age. There is no prior history of influenza vaccination. Maria's nurses do not want to miss this opportunity to make sure she is current on her immunizations before discharge. But they are concerned about administering vaccines with no access to Maria's thighs. Here are three questions about Maria. What vaccines are indicated for Maria? What sites should be used to administer the vaccines she needs today? And when should Maria be scheduled for her next immunization visit? 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. Maria is an immunization nurse's nightmare. She needs several vaccines but her largest muscle mass is inaccessible. In this situation you do not defer the vaccine she needs but injection technique becomes of paramount importance. Here is the first question about Maria. What vaccines are indicated for Maria? Maria needs her fourth dose of DTAP pneumococcal conjugate and her first doses of influenza, MMR, and varicella vaccines. She could also be considered for her first dose of hepatitis A vaccine. Maria is complete for hepatitis B. She actually received four doses with the birth dose and the pediatrics series. The birth dose and the doses at two months and six months count as the three valid hepatitis B doses. Maria also received three doses of DTAP and IPV in the pediatrics. She is current for IPV but behind for the fourth dose of DTAP. Maria has completed the HIB series but she has received no doses of PCV. Since she is healthy in two years of age she only needs a single dose of PCV. Now for some reason Maria did not receive her first doses of MMR and varicella at 12 months of age so she definitely needs those now. It is influenza season and there is an outbreak in the community so Maria needs protection against influenza. Maria did not receive the hepatitis A vaccine series at 12 to 23 months of age as recommended but children two years of age and older can be considered for catch-up. The only other routine vaccine for young children is rotavirus vaccine but Maria is too old to begin the rotavirus vaccine series. Here's the second question about Maria. What sites should be used to administer the vaccines she needs today? Maria will need vaccines to be administered in the deltoid muscles of both arms the posterior upper triceps area of the arms and the nose. Maria can receive DTAP by the IM route in one deltoid and PCV IM in the other deltoid. MMR can be given subq in the triceps area of one arm and varicella subq in the triceps area of the other arm. For influenza Maria can receive live attenuated influenza vaccine by the intranasal route. It is very important that DTAP and PCV be given by the intramuscular route. These vaccines contain an adjuvant and are likely to cause a local reaction if given by the subcutaneous route. Since Maria is in a cast from waist to knees the thighs are not accessible for vaccination. The deltoid muscles are not routinely used for IM injections in a two-year-old but can be used if the muscle mass is adequate. In Maria's case you do not have a choice since her antralateral thighs are not accessible. Now some hospitals and agencies may have a policy that does not include use of the deltoid muscle for IM injection in infants and toddlers. In these situations a specific written order may be required. Because the deltoid muscle in a two-year-old is typically small generally only one IM injection would be administered in this site. The needle size should be selected based on the size of the muscle and the thickness of adipose tissue at the injection site. You will find guidance on this in the ACIP general recommendations. If MMRV is available, the MMR-Vericella Combination Vaccine, it can be used for one sub-q injection instead of two. The fact that Maria's mother is pregnant is not a contraindication to any of the vaccines and neither is the grandmother's immunosuppression. Maria has no contact with anyone in protective isolation so there is no contraindication to using LAIV. And here's the third question about Maria. When should Maria be scheduled for her next immunization visit? Maria needs to return in four weeks to receive her second dose of influenza vaccine. The recommended interval between doses of influenza vaccine for a child being vaccinated for the first time is now four weeks for either LAIV or inactivated vaccine. Either LAIV or TIV could be used for the second dose. A healthy child beginning the pneumococcal conjugate vaccine series at 24 to 59 months of age needs only one dose so the one you give today is all she needs. Bill? Donna we know that a lot of facilities don't stock LAIV. In the case of Maria, if they didn't have LAIV now what do you do about her influenza vaccine? The plot thickens. Well there is an influenza outbreak in the community so Maria definitely needs influenza vaccine before she goes home. I would use the injectable form. This means Maria will receive three I.M. injections. You could give PCV in one deltoid and TIV and DTAP in the other deltoid. Now if there's concern about adequate muscle tissue you could delay a DTAP-4 until the follow-up visit four weeks later. Maria has already had three doses of DTAP so delaying DTAP number four could be considered but she has received no doses of PCV so it should be a priority. Now this would put you back in the situation of three I.M. injections at the follow-up visit. TIV-2, DTAP number four and the first dose of hepatitis A vaccine. The hepatitis A vaccine could be deferred until her next visit but if you keep putting off vaccine doses you run the risk Maria won't get them at all. You have to weigh the option of giving two I.M. injections in one deltoid muscle against the risk of a missed opportunity and this will have to be a case-by-case clinical judgment. Thanks tough tough decision. Happens though. We get lots and lots of questions about hepatitis A and B vaccines. Andrew what do you do about a person who claims to have had hepatitis A and then is going to travel to some high-risk area? How do you handle that situation? Well it's a great question. You want to be sure they've actually had hepatitis A. If they have indeed had hepatitis A disease they would be immune and would not need further vaccination but you'd like to be sure you'd like it to be serologically documented. If you are uncertain then you definitely want to give a dose of hepatitis A vaccine. You could do a serologic test to confirm immunity as well. Okay Donna what is the rationale for recommending hepatitis A vaccine to a person with chronic liver disease if they're not otherwise at risk? Yeah they are not at increased risk for infection but the problem is that their liver is already you know insulted so if if they were to become infected it could really cause problems so you want to protect that liver as much as you can so that's why the vaccine is recommended for them. Risk of complications. One additional question for only one of the most common we get. We get lots of requests by people who work around sewage to be vaccinated against all kinds of things. Hepatitis A, typhoid, hepatitis B. What do you say to these individuals who are in contact with human waste? Andrew? Great question. People in contact with human waste, sewage workers, plumbers, they do not have an occupational risk. They're not indicated for hepatitis A on that basis alone. Of course if other risk factors exist they may be indicated for hepatitis by virtue of occupation that alone is not a risk factor. You may want to make sure that they are definitely up to date on their TD vaccination either the primary series or the booster because they would be at risk of tetanus so that would definitely be something you'd want to do. Okay good answer thanks Andrew, thanks Donna. Despite the availability of an effective vaccine for more than 50 years influenza remains the most common vaccine preventable cause of death in the United States. A continuously changing virus creates a challenge to both vaccine manufacturers and to healthcare providers who want to protect their patients. Influenza is a highly infectious acute viral illness. Epidemics of what was probably influenza have been reported since at least the 1700s. There have been at least three global epidemics known as pandemics in the last 100 years. What is often cited as the biggest and deadliest pandemic of all time the 1918-1919 pandemic of so called Spanish influenza is believed to have killed an estimated 50 million people worldwide. Influenza is an orthomixovirus which was first isolated in 1933. There are three types A, B and C. Type A causes moderate to severe illness in all age groups. Type B generally causes milder epidemics and primarily affects children. Type C does not cause epidemics and is rarely reported in humans so we will not discuss it further. Type A has subtypes which are determined by two surface antigens hemagglutinin and neuraminidase. This is an illustration of the surface of the influenza virus. Hemagglutinin, the blue spikes help the virus attach to cells. Neuraminidase, the green knobs facilitate the release of mature virus from infected cells. Three types of hemagglutinin and two types of neuraminidase have been described for human influenza viruses. Type A influenza viruses are grouped or subtyped depending on the type of H and N they have. For instance, one of the current strains of influenza A virus has type 3 hemagglutinin and type 2 neuraminidase. This virus is identified as H3N2. A person's immunity to the surface antigens, particularly hemagglutinin, reduces the likelihood of infection with influenza virus and reduces the severity of disease if infection occurs. Antibody against one influenza virus type or subtype provides little or no protection against another type or subtype. Unfortunately, the structure of the surface antigens changes with time. These changes allow influenza virus to evade our immune response to prior influenza infection or vaccination. The result is that most of us will experience repeated infections with influenza viruses throughout our lifetime and the components of the vaccine must be frequently changed. There are two types of antigenic changes that the influenza virus undergoes. Drift and shift. Antigenic drift is a relatively minor change within the same subtype. It results from point mutations in the gene coding for hemagglutinin and occurs during viral replication. Antigenic drift may be associated with epidemics depending on how different the new virus is from the prior one. Drift occurs continually from year to year or even within the same year. Antigenic shift is a major change which creates a new virus subtype. This new subtype usually replaces its predecessor. Antigenic shift is probably due to genetic recombination between human and non-human influenza viruses. This type of change is associated with pandemics because the entire population of the world is susceptible to this new virus. These major changes do not happen frequently but when they do a major pandemic may follow. There have been three antigenic shifts in the last 100 years which occurred about every 10 to 40 years. The last major shift was in 1968. Influenza experts believe it is not a question of if influenza virus will shift again. It is only a matter of when the shift will occur. There is concern that a new pandemic virus could be evolving. In late 2003 and early 2004 outbreaks of highly pathogenic avian influenza caused by the influenza A H5N1 strain occurred among poultry in nine countries in Asia. At that time more than 100 million birds either died from the disease or were destroyed as part of the control effort. Since that time the virus has been detected in migratory and domesticated birds as far west as the United Kingdom Spain and the Ivory Coast. As of March 2nd 2009 a total of 409 human infections with H5N1 virus have been confirmed. 256 or 63 percent of the infected persons have died. The largest annual total reported was in 2006 with 115 human infections. A total of 44 human infections was reported worldwide in 2008. Infections have been reported from 14 countries mostly in Asia. Since 2006 about half of all reported cases have occurred in Indonesia. To date no infections caused by the highly pathogenic form of H5N1 have been reported in the United States. All evidence to date indicates that close contact with dead or sick birds is the principal source of human infection with H5N1 virus. It is believed that limited human-to-human transmission may have occurred on two occasions in Thailand and Indonesia, but transmission has not been sustained. It is not known if H5N1 will be the next pandemic virus, but even if it is not a new pandemic virus will arise eventually so we need to be ready for it. We will come back to this issue a little later. Yabo. Thanks Andrew. The clinical features of influenza run the gamut from mild to severe or even fatal. Infection with influenza virus can also lead to life-threatening complications. Transmission of influenza is by respiratory droplets. The incubation period is short one to four days. There is usually an abrupt onset of fever, myalgia, sore throat, non-productive cough, and headache. The severity of illness from influenza depends on prior immunologic experience with energenically related variants. That means that if you're exposed to a drifted strain similar to the one you had the year before, the illness will probably be mild. But if the virus is drifted a lot or were shifted, the illness may be severe even if you had influenza or were vaccinated the previous year. Influenza is a respiratory disease and the major complication is pneumonia. It can either be primary influenza pneumonia or secondary bacterial pneumonia commonly due to pneumococcus. Rye syndrome is an infrequent complication and occurs in children taken aspirin. Myocarditis is inflammation of the heart and is a relatively rare complication. Overall, death from influenza occurs once in every one to two thousand cases but is much more frequent in certain populations. Influenza is the most frequent cause of death from a vaccine preventable disease in the United States. During 1990 through 1999 approximately 36,000 influenza associated pulmonary and circulatory deaths occurred during each influenza season. Influenza seasons in which H3N2 viruses predominate are associated with higher mortality. Person 65 years of age and older account for more than 90 percent of deaths attributed to pneumonia and influenza. Persons with underlying medical conditions account for most of the remaining 10 percent of deaths. In addition to fatalities, influenza is also responsible for an average of more than 200,000 hospitalizations per year. Although persons 65 years and older are at the highest risk of dying from influenza, other age groups are at nearly as high risk for influenza associated hospitalization. Rates of hospitalization among children two years and younger are very high and are similar to those of persons 65 and older with high risk medical conditions. The increased risk of hospitalization for children extends at least through four and possibly five years of age. In addition, children 24 through 59 months of age are at increased risk for influenza related clinic and emergency department visits. Rates of serious illness and death are highest among persons 65 years and older. Children younger than two years and persons of any age who have medical conditions that place them at increased risk for complications from influenza. Healthy children five through 18 years of age are not at increased risk of complications of influenza. However, children typically have the highest attack rates during community outbreaks of influenza. They also serve as a major source of transmission of influenza within communities. This graphic shows influenza infection rates by age groups from two different multi-year community-based studies conducted during the 1960s and 1970s. A study conducted in Houston is shown on the yellow line and Tecumseh Michigan is shown in the red line. In both studies the highest influenza attack rates up to 40 percent occurred among children five through 14 years of age. Influenza has a substantial impact among school-aged children and their contacts. These impacts include school absenteeism, medical care visits, and parental work loss. Studies have documented five to seven influenza-related outpatient visits per 100 children annually and these children frequently receive antibiotics. In addition to the direct benefits of influenza vaccination of school-aged children there could be indirect health benefits if sufficient vaccination coverage among children can be achieved. Studies have demonstrated reductions in influenza-like symptoms and medical visits among household contacts and communities where vaccination programs among school-aged children were established. It is for these reasons that the advisory committee on immunization practices expanded this recommendation for routine influenza vaccination to include children through 18 years of age. In summary influenza is a disease caused by a virus that changes continuously. Influenza virus is responsible for thousands of deaths each year even without a major energetic change. Highest rates of influenza illness occur in school-aged children but most complications and deaths from influenza occur in persons 65 and older those with underlying illnesses and young children. Donna? Inactivated influenza vaccine has a longer history than most vaccines we use. The first effective influenza vaccines were produced in the mid 1930s. The discovery in the 1940s that influenza virus grew well in embryo-nated chicken eggs allowed large-scale production of inactivated influenza vaccines. Influenza became the first genetically engineered vaccine in 1971 when this technique was used to improve virus yields needed for vaccine production. There are two main types of influenza vaccine available in the U.S. A live attenuated influenza vaccine abbreviated LAIV and an inactivated subunit vaccine which we will abbreviate TIV. There are two subtypes of TIV. These two subtypes contain either split virus or purified surface antigens. Live attenuated influenza vaccine was licensed by the Food and Drug Administration in 2003 and was the first commercial vaccine to be administered by a nasal spray. The vaccine is produced by Metamune and marketed with the brand name FluMist. The vaccine viruses in LAIV have been genetically modified to replicate in the upper airway, not in the long. All current influenza vaccines are trivalent, meaning that they contain three different viruses H3N2, H1N1, and B. The viruses contained in the vaccines are chosen each spring based on surveillance of current circulating strains. Vaccine efficacy varies. Efficacy depends on the recipient and the similarity of the vaccine virus to the circulating virus. The duration of immunity for inactivated influenza vaccine is considered to be one year or less. The duration of immunity appears to be at least one year for LAIV. In a clinical trial of LAIV among children there was evidence of efficacy during a second influenza season. Following inactivated influenza vaccination antibody wanes in a few months and may fall below protective levels. The virus may also drift so the antibody to the vaccine virus is less effective. This would apply to both LAIV and TIV. The efficacy of inactivated influenza vaccine and preventing clinical illness also depends on several recipient factors. Age and underlying illness are the main recipient factors. For example, if there is a good match between the inactivated vaccine and circulating influenza strains the inactivated vaccine is 70 to 90 effective in preventing clinical illness among healthy persons younger than 65 years of age. The problem is that it is only 30 to 40 effective in preventing illness among older persons who reside in long-term care facilities. However, TIV has been shown to be up to 80 effective in the prevention of complications and deaths from influenza even among these older persons. Limited studies have compared the ability of LAIV and TIV to protect adults 18 to 41 years of age against laboratory confirmed influenza. Overall LAIV was 85 effective and TIV was 71 effective. There was no statistically significant difference in vaccine efficacy between the two types of vaccine. The takeaway message for either type of influenza vaccine is that they may not prevent illness as well as we would like but vaccinated persons have milder illness and significantly fewer complications as a result of the infection. For the 2008-2009 influenza season four manufacturers produced more than 100 million doses of inactivated influenza vaccine. This amount of vaccine is likely to be available during the next influenza season as well. Three manufacturers produce multiple presentations and three of the four have different age indications for their products. Santa Fe Pasteur produces flu zone which is available in four presentations. The first is a multi-dose vial that contains thimerosol as a preservative. This formulation may be administered to anyone six months of age or older. Flu zone is also available in three thimerosol free formulations. Single-dose syringes with a 0.25 milliliter pediatric dose of vaccine for children six through 35 months of age and single-dose syringes and vials with a 0.5 milliliter dose for persons 36 months and older. Fluviron is produced by Novartis. It is available in a multi-dose vial that contains thimerosol and as a prefilled syringe that does not contain thimerosol as a preservative. Both presentations are licensed for persons four years and older. Fluorix is produced by Glaxospithclin and is available only in a single-dose syringe. Glaxo also produces flulovol in a multi-dose vial. Both vaccines are approved for persons 18 years and older. The flulovol multi-dose vial contains thimerosol as a preservative. Fluorix does not contain thimerosol as a preservative. Afluria is produced by CSL biotherapies. Afluria is available in a single-dose syringe and in a multi-dose vial. Both vaccines are approved only for persons 18 years and older. The multi-dose vial contains thimerosol as a preservative. The single-dose syringe presentation is preservative-free. You should be careful to administer these vaccines only to persons in the age group for which they are approved. If you intend to administer inactivated influenza vaccine to children younger than four years of age, you must use Fluzone. None of the other inactivated vaccines are approved for children this age and ACIP does not recommend use of these vaccines outside their approved age ranges. Andrew? The schedule for an activated influenza vaccine is relatively simple. One intramuscular dose per year. But the dose is not the same for all age groups and some persons need two doses. Here is the routine schedule for an activated influenza vaccine. The minimum age is six months. No influenza vaccine is approved for children younger than six months of age. Children six months through 35 months of age receive a 0.25 milliliter dose, half the dose of an older child or adult. Recipients three years of age and older should receive a 0.5 milliliter dose. Children six months through eight years of age receiving TIV for the first time should receive two doses separated by four weeks. The first dose is an immunologic primer. Children three through eight years should receive one or two doses depending on their previous vaccination history. Persons nine years of age or older receive one annual dose because by this age their immune system has been primed by infection with wild type influenza virus. We receive many questions about administration of a second dose of TIV in the same season, particularly among high-risk persons vaccinated in September or October. There are a few data to support the need for a second dose in a season. ACIP does not recommend administration of more than one dose of influenza vaccine per season for any group except children six months through eight years of age receiving influenza vaccine for the first time. Despite your best efforts, some children six months through eight years of age who need two doses of influenza vaccine do not return for their second dose. Children six months through eight years of age who did not receive the recommended second dose of influenza vaccine in the initial year that they received influenza vaccine should receive two doses during the next influenza season. This recommendation applies only to the influenza season that follows the first season that a child younger than nine years receives influenza vaccine. This recommendation applies to both inactivated and live attenuated influenza vaccine. Children six months through eight years of age who are being vaccinated two or more seasons after receiving an influenza vaccine for the first time should receive a single annual dose regardless of the number of doses administered previously. This new recommendation has caused some confusion among clinicians vaccinating children. We want to be sure you are clear on it. Here are three examples. A child six months through eight years of age received her only dose of vaccine last year. This year she should get two doses separated by four weeks. A child was vaccinated for the first time two years ago. She received one dose that year and one dose last year. This year in all subsequent years she will receive only one dose. Finally a child was vaccinated for the first time two years ago. She received only one dose that year and no influenza vaccine last year. This year in all subsequent years she should receive one dose. Live attenuated influenza vaccine or LAIV is an option for some persons who want to lower their risk of influenza. However LAIV has a limited age range and cannot be administered to persons with underlying medical conditions. Live attenuated influenza vaccine is approved for healthy persons two through 49 years of age. Do not administer LAIV to children younger than two years or to adults older than 49 years. The dose of LAIV is 0.2 milliliter divided equally between the nostrils. The dose is the same regardless of age. Children two through eight years of age who have not previously received any type of influenza vaccine should receive two doses of LAIV separated by at least four weeks. Children two through eight years of age who have previously received influenza vaccine should receive one or two doses of LAIV depending on the number and timing of the previous doses. One dose is recommended for persons nine through 49 years of age because it is presumed they have already been primed through exposure to wild type viruses. A child receiving influenza vaccine for the first time may not return for the second dose four weeks later. The same rule applies to this situation as with inactivated influenza vaccine. If the child does not receive two doses in the first vaccination year he or she should receive two doses of influenza vaccine the next year. If the child does not return for two or more years he or she should receive one dose of influenza vaccine that year and all subsequent years. Yabo? With the recommendation to vaccinate all children six months through 18 years of age influenza vaccine is now recommended for about 83% of the U.S. population. Although there is overlap the target groups are different for TIV and LAIV. Influenza vaccine should be provided to all persons who want to reduce the risk of becoming ill with influenza or of transmitting it to others. However emphasis should continue to be on providing routine vaccination annually to certain groups at higher risk for influenza infection or complications and persons in contact with these high risk groups. The risk factors for severe illness and complications from influenza are age, chronic illness, pregnancy, and aspirin use in children. We'll show you the specifics in the next few graphics. The targeted groups for TIV include all persons 50 years of age or older, persons six months of age and older with certain chronic illnesses and healthy children six months through 18 years of age. Persons with certain chronic illnesses should receive an activated influenza vaccine. Chronic illnesses include pulmonary disease such as emphysema and asthma, cardiovascular disease, and metabolic diseases like diabetes. They also include renal dysfunction like chronic renal failure on nephropathy, hemoglobinopathy such as sicker cell disease, and immunosuppression including HIV. Available data suggests that persons with HIV infection may have prolonged influenza illness and are at higher risk of complications of influenza. Clinical trials of persons with HIV infection have demonstrated that even those with low CD4 T cell counts respond well to an activated influenza vaccine. Although a transient increase in HIV replication has been reported, there is no evidence of deterioration in the CD4 count and no progression of clinical HIV disease. ACIP believes that an activated influenza vaccination will benefit many persons with HIV infection including pregnant women. LAIV should not be administered to persons with HIV infection. ACIP recommends vaccination of persons with any condition that can compromise respiratory function or the handling of respiratory secretions or that can increase the risk of aspiration. This would include persons with cognitive dysfunction, spinal cord injury, seizure disorder, or other neuromuscular conditions. In addition to persons 50 and older and persons with chronic illness, the target group for TIV includes residents of long-term care facilities, persons 6 months through 18 years of age receiving chronic aspirin therapy because of their risk of RISE syndrome, and pregnant women. Pregnant women are a group at increased risk for complications of influenza. Excess deaths from influenza among pregnant women were documented during the pandemics of 1918 through 1919 in 1957 to 1958. Case reports and limited studies also indicate that pregnancy can increase the risk for serious medical complications of influenza. A study published in 1998 found that the risk of hospitalization for influenza-related complications was more than four times higher for women in the second or third trimester of pregnancy than for non-pregnant women. The risk of complications for these pregnant women was comparable to non-pregnant women with high risk medical conditions. ACIP recommends vaccination of all women who will be pregnant during the influenza season. Only inactivated influenza vaccines should be administered to pregnant women. LAIV is contraindicated for pregnant women. Inactivated influenza vaccine distributed in multi-dose vials contains thimerosal as a preservative. Thimerosal-free formulations and formulations with only a trace of thimerosal are also available. Any of these formulations can and should be administered to pregnant women. It is ACIP's opinion that the benefit of influenza vaccination of a pregnant woman outweighs the theoretical risk to a fetus from exposure to the small amount of thimerosal in a dose of influenza vaccine. Other groups to consider for influenza vaccination include providers of essential community services, international travelers and persons in institutional settings such as students. Finally, assuming that supplies are sufficient, anyone who wants to reduce the likelihood of influenza may be vaccinated. If the persons in these latter groups are two through 49 years of age, healthy and not pregnant, they would be candidates for LAIV. Use of LAIV in healthy persons could help conserve TIV for the groups who are not able to receive LAIV. Donna? The primary objective of influenza vaccination is to protect those at highest risk of complications and death from influenza. The second objective is to prevent influenza in the persons who might transmit the virus to these high-risk groups. Here are the persons who, when immunized, help protect the highest risk groups from exposure to influenza. Vaccinated household members of high-risk persons could keep influenza out of the home. This includes all household members of children younger than five years of age, particularly infants. These household members are a group for whom LAIV could also be used. Healthcare personnel, including home care providers, are a critical group to be vaccinated. Finally, employees of long-term care facilities should be vaccinated. This applies not only to the nurses and doctors. Do not forget the medical assistants, housekeepers, physical therapists, dieticians, and anyone else who shares error with the patients. Healthcare personnel are a high priority for early supplies of influenza vaccine. Healthcare personnel are often implicated in introducing influenza into healthcare settings and causing outbreaks among patients. Outbreaks among patients have been reported in a number of healthcare settings, including ICUs, natal intensive care units, and long-term care facilities. Yet influenza vaccination levels among healthcare personnel are abysmally low. Vaccination of healthcare personnel is a high priority for reducing the effect of influenza in healthcare settings. We do not have time during this program to go into detail on this issue, but many resources are available to help increase influenza vaccination levels among healthcare personnel. In 2006, the ACIP published a document that specifically addresses the issue of influenza vaccination of healthcare personnel. It includes specific recommendations that can help improve influenza vaccination levels in your facility. In addition, we have included a presentation on influenza vaccination of healthcare personnel on the DVD of this program. The presentation is also available on the updates and resources webpage. If you are responsible for influenza vaccination of employees in your facility, please review these resources. Another important component of our annual influenza vaccination program is its timing. In any given year, the optimal time to vaccinate for influenza cannot be determined because influenza seasons vary in their timing and duration. In addition, more than one outbreak might occur in a community in a single year. In the United States, localized outbreaks that indicate the start of seasonal influenza activity can occur as early as October. However, in more than 80 percent of influenza season since 1976, peak influenza activity has not occurred until January or later, and in more than 60 percent of seasons the peak was in February or later. In general, immunization providers should begin offering vaccines soon after it becomes available and if possible by October. To avoid missed opportunities for vaccination, providers should offer vaccine during routine healthcare visits or during hospitalizations whenever vaccine is available. Persons planning organized vaccination campaigns such as health departments, occupational health clinics, and community vaccinators should consider scheduling these events after at least mid-October. This is because the availability of vaccine in any location cannot be ensured consistently in early fall. Scheduling campaigns after mid-October will minimize the need for cancellations because vaccine is unavailable. ACIP recommends that providers continue to offer influenza vaccine in December, especially to healthcare personnel and those at high risk of complications. Providers should continue to vaccinate throughout influenza season, typically December through March, even after influenza activity has been documented in the community. Vaccine administered in December or later, even if influenza activity has already begun, is likely to be beneficial in the majority of influenza seasons. The majority of adults have antibody protection against influenza virus infection within two weeks after vaccination. Planners are encouraged to develop the capacity and flexibility to schedule at least one vaccination clinic in December. CDC has developed guidelines for planning large-scale immunization clinics. We will provide a link to these guidelines on our update and resources webpage. Yabo? The ACIP believes that live attenuated influenza vaccine can be an important adjunct to the use of inactivated influenza vaccine. However, LAIV is not a substitute for an inactivated influenza vaccine since it cannot be administered to persons at highest risk of complications of influenza. LAIV is currently approved for use only for non-pregnant, healthy persons two years through 49 years of age. This group includes healthy children, healthcare personnel, and other persons in close contact with high-risk groups such as household contacts. The vaccine is also an option for healthy persons who want to reduce their risk of influenza. These persons now have the option of choosing either TIV or LAIV. LAIV should not be used in children younger than two years or adults 50 years of age and older. It also should not be used in anyone with an underlying medical condition that increases the person's risk of complications of influenza. TIV should be used for these groups. There have been concerns about transmission of live attenuated influenza vaccine viruses to close contacts, particularly in a healthcare setting. These concerns have been unfounded. CDC has received no reports of transmission of vaccine viruses in any setting. As a result, ACIP recommends that otherwise eligible healthcare personnel and others with close contact with high-risk persons including immunosuppress persons consider receiving LAIV. The exception to this recommendation is that inactivated influenza vaccine is preferred for close contacts of severely immunosuppressed persons who require care in a protective environment. There are no data on the effect if any of LAIV on a tuberculin skin test. Until additional data become available, we recommend that you apply the same rules to LAIV that you use for MMR and varicella vaccines. Apply a tuberculin skin test before or at the same visit as LAIV. Defer the skin test for at least four weeks if LAIV has already been administered. The adverse reaction profile for the inactivated influenza vaccine is not much different from other inactivated vaccines. As you would expect from any inactivated vaccine, the most common adverse reactions are local reactions. 15 to 20 percent of TIV recipients report local reactions like pain and redness at the injection site. Systemic reactions like fever and malaise are not common. They occur most commonly in persons without prior exposure to the antigens in the vaccine, particularly young children. Severe allergic reactions are rare and are most likely related to residual egg protein when they do occur. Good screening can essentially eliminate the risk of allergic reactions and influenza vaccine recipients. Neurologic reactions specifically Guillain-Barre syndrome are very rare. GBS has not been clearly associated with the inactivated influenza vaccine since the swine flu vaccine in 1976. TIV is inactivated so it cannot cause influenza. However, it is possible to get influenza after vaccination. It takes a week or two to develop a good immune response to the vaccine. But since the incubation period is only a few days, you could get flu if you were exposed shortly after vaccination before the vaccine has a chance to work. In some clinical trials among children younger than 59 months of age, LAIV recipients had a significantly increased risk of asthma or reactive airways disease. In a trial comparing LAIV and inactivated influenza vaccine, 6% of children 6 through 23 months of age who received LAIV develop wheezing that required bronchodilator therapy or that was associated with significant respiratory symptoms. 4% of children who received inactivated influenza vaccine developed wheezing. This observation resulted in a contraindication to LAIV for children younger than five years with a history of reactive airways disease. We will discuss this in more detail in a moment. In some studies of adults, LAIV recipients experienced statistically significant increase rates of cough, chorizo, nasal congestion, sore throat, and chills. No increase in the occurrence of fever has been identified among adults. LAIV contains live attenuated influenza viruses that replicate in the upper airway. Although not technically an adverse reaction, you should be aware that receipt of LAIV could result in a positive influenza antigen screening tests. But this should not be a common problem because influenza screening should be performed only on persons with an influenza-like illness. While it is possible for an LAIV recipient to be infected with influenza virus, the LAIV itself would not be expected to cause an influenza-like illness. Donna? Contraindications and precautions differ between inactivated and live attenuated influenza vaccines. Those to TIV are the same as most other inactivated vaccines. A history of a severe allergic reaction to a vaccine component or following a prior dose of vaccine is the only contraindication. Needless to say, persons with a severe egg allergy should not receive influenza vaccine. Moderate or severe acute illness is a precaution and vaccination should be deferred until the acute illness has improved. A history of Guillain-Barre syndrome or GBS within six weeks following a previous dose of TIV is considered to be a precaution for use of TIV. The incidence of GBS among the general population is very low, but persons with a history of GBS have a substantially greater likelihood of subsequently developing GBS than persons without such a history. So the likelihood of coincidentally experiencing GBS after influenza vaccination is expected to be greater among persons with a history of GBS than among persons without a history. Whether influenza vaccination increases the risk for recurrence of GBS is not known. However, avoiding vaccinating persons who are not at high risk for severe influenza complications and who are known to have experienced GBS within six weeks after a previous influenza vaccination is prudent. As an alternative, clinicians might consider using influenza antiviral chemoprophylaxis for persons who previously developed GBS after influenza vaccination. Although data are limited, the established benefits of influenza vaccination generally outweigh the risk for many persons who have a history of GBS and who are also at high risk for severe complications from influenza. There's quite a long list of contraindications for LAIV. It might help to think of LAIV as being contraindicated for most persons for whom inactivated influenza vaccine is indicated. TIV should be considered in most persons for whom LAIV is contraindicated. As with all vaccines, a severe allergic reaction to a vaccine component or following a prior dose is a contra indication for LAIV. The viruses in LAIV are grown in chicken eggs, so severe egg allergy would be a concern, like it is for TIV. LAIV is contraindicated for children 18 years and younger receiving chronic aspirin therapy because of the risk of Rye syndrome. Precautions to LAIV include underlying medical conditions that predispose the person to complications of influenza, immunosuppression from any cause, and pregnancy. Pregnant women should not receive LAIV but should be routinely vaccinated with TIV. Other precautions to LAIV include a history of Guillain-Barre syndrome and the presence of a moderate or severe acute illness. LAIV can be administered to persons with minor acute illnesses. But if you believe that nasal congestion is present in such a degree as to impede delivery of the vaccine, defer administration until the illness improves. Finally, asthma or recurrent wheezing in children younger than five years is a precaution for LAIV. Healthy children younger than five years who received LAIV in clinical trials appear to have an increased risk of wheezing. The risk, if any, of wheezing caused by LAIV among children of this age with a history of asthma or recurrent wheezing is unknown because experience with the vaccine among these children is limited. Young children might not have a history of recurrent wheezing if their exposure to respiratory viruses has been limited because of their age. Some children might have a history of wheezing with respiratory illnesses but have not had asthma diagnosed. Clinicians and immunization programs should avoid use of LAIV in children with asthma or a recent wheezing episode. The ACIP developed screening recommendations to assist persons who administer influenza vaccines in providing the appropriate vaccine for children two through four years of age. Healthcare providers should consult the medical record when available to identify children two through four years of age with asthma or recurrent wheezing that might indicate asthma. In addition to identify children who might be at greater risk for asthma and possibly at increased risk for wheezing after receiving LAIV, parents or caregivers of children age two through four years should be asked, in the past 12 months has a healthcare provider ever told you that your child had wheezing or asthma? Children whose parents or caregivers answer yes to this question or whose medical record notes asthma or a wheezing episode within the past 12 months should not receive LAIV. Inactivated influenza vaccines should be administered to children with asthma or possible reactive airways diseases. This issue as well as other information regarding use of LAIV among children two through four years of age is discussed in the influenza ACIP statement. We will include a link to it on the updates and resources webpage. Andrew? Like other live virus vaccines, the vaccine viruses in LAIV are fragile so storage and handling of this vaccine is critical. Both types of influenza vaccine live attenuated and inactivated must be stored at refrigerator temperature at all times. Refrigerator temperature is 35 to 46 degrees Fahrenheit or two to eight degrees Celsius. Neither vaccine should be frozen. Inactivated influenza vaccine exposed to freezing temperature must not be used. If LAIV is inadvertently frozen the vaccine should be placed at refrigerator temperature and used as soon as possible. Because LAIV is administered intranasally using a sprayer device low level contamination of the environment with vaccine virus is probably unavoidable. This has caused concern about unintentional exposure to persons administering the vaccine. The risk of acquiring vaccine virus from the environment is not known but is likely to be limited. ACIP recommends that severely immunosuppressed persons should not administer LAIV. Practically that means that if a person is immunocompetent enough to go to work he or she is immunocompetent enough to administer LAIV. Other persons at increased risk of complications of influenza may administer LAIV including pregnant women, persons with asthma, and persons 50 years of age and older. Of course these persons should have already received the dose of inactivated influenza vaccine. Gloves and masks are not required to administer LAIV. As we mentioned earlier there is little doubt that the influenza virus will shift again and that there will be another influenza pandemic in the future. The problem is that we do not know when it will happen. Although we cannot predict when the next pandemic will occur we can try to prepare for it. The Department of Health and Human Services has released both a national pandemic strategic plan and an implementation plan. The documents are extensive and will be very useful to anyone involved in pandemic planning at any level of public health. We will include a link to these materials on our updates and resources webpage. We would like to present a case study that addresses some of the issues that we have discussed during this program. The case studies are available on the updates and resources webpage for this program. Michelle is 22 years old and is beginning nursing school. She has mild asthma which is controlled with the occasional use of an epidural inhaler. She was told by her parents that she had chickenpox at age five years but has no documentation of this. Michelle has a written record of having received five doses of DTP, five doses of OPV and two doses of MMR in childhood and a hepatitis B vaccine series, three doses at age 12 years. The nursing school requires serologic proof of hepatitis B immunity. Her test for antibody to hepatitis B surface antigen or anti-HBS drawn one month ago is negative. Here are the questions. What vaccine or vaccines should Michelle receive today? What if any serologic testing should be done at today's visit? And when should Michelle return and what vaccine or vaccines should she receive at that visit? If you're 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. The situation described in this case study is not an unusual one. Fortunately Michelle has her childhood vaccination record. Unfortunately the school required her to have hepatitis B serologic testing even though she has written documentation of having received the hepatitis B vaccine series. Here's the first question about Michelle. What vaccine or vaccines should Michelle receive today? Today she should receive a dose of Tdap either adicel or boostrix and a dose of hepatitis B vaccine. She should also receive pneumococcal polysaccharide vaccine because of her asthma. If it is influenza season she needs influenza vaccine because of her asthma and her work in healthcare. She should receive only an activated influenza vaccine. She is also eligible for her first dose of human papillomavirus vaccine. Although Michelle is older than the age for routine Tdap vaccination she needs a dose because she is entering nursing school. Unfortunately the school required her to be tested for hepatitis B immunity even though she had written documentation of vaccination. The ACIP does not recommend serologic testing years after vaccination but since it has been done she should receive a dose of hepatitis B vaccine today as well. Here's the second question about Michelle. What if any serologic testing should be done at today's visit? Today she should have blood drawn for varicella Ig antibody. Michelle does not meet any of the criteria for varicella immunity for healthcare personnel namely documented vaccination or varicella azoster diagnosed or verified by a clinician. She is likely to have had chickenpox based on the history so testing for IgG antibody to varicella is likely to confirm her varicella immunity. Here's the third question about Michelle. When should Michelle return and what vaccine or vaccines should she receive at that visit? Michelle should return in one to two months for the results of her varicella serologic testing. She may need her first dose of varicella vaccine if the serology is negative. She can also receive her second dose of HPV vaccine. She should also have a repeat anti-HPS test for hepatitis B immunity at that time. If Michelle's varicella IgG is negative she will need two doses of varicella vaccine separated by at least four weeks. If more than four weeks has passed the second dose of HPV could be given but it is preferable to wait until the recommended two-month interval if possible. It is likely that her repeat anti-HPS will be positive. Most children respond to the hepatitis B series but the antibody level can wane in the years that pass since vaccination. The single dose of hepatitis B vaccine will boost her antibody back into the detectable range. Michelle should be given a copy of her positive anti-HPS lab report and instructed to keep it forever since she will almost certainly need to document her immunity for an employer in the future. It is possible that the repeat anti-HPS could come back negative although vaccine failure in children is unusual. If this is the case Michelle will need to complete a second series of three doses and be tested again at the completion of the second series. Yabo, you mentioned that Michelle needs pneumococcal polysaccharide vaccine because she has asthma. Is she going to need a revaccination dose at some point in time? Good question, Andrew. Yes, she will need a revaccination dose at the age of 65. That's the current recommendation for one revaccination dose. So for asthma you get one revaccination dose later after age 65? That's all right. Another question about this very interesting case. You mentioned it's unfortunate that Michelle had anti-HPS testing. Obviously she did receive it but it seems like it wasn't necessary. Can you talk a little bit more about that? Sure, we get this question often and the reason I mentioned that is I stated in the case study routinely we do not recommend post-vaccination anti-HPS testing especially if someone had the vaccine years prior. If testing is to be done it all is recommended one to two months after the last final dose in the three-dose series of hepatitis B. Doing it so long after the series is completed you'll run the risk of where the antibody levels may be low not because she's lost immunity but just because of waning and so that's why it's not recommended. Got it. A couple questions about influenza Donna. If someone has already had influenza vaccine will they still need influenza rather if they've already had influenza disease will they still need influenza vaccine? Yes we still recommend even though they have a history of disease that they be vaccinated because you know the vaccine protects against three different two strains of A strains of influenza virus and the B strains so you know if they've been infected there's still two other strains in there that would protect them and that is if they were infected with one of the vaccine strains now it's possible that they could have been infected with something that isn't even in the vaccine and and then the vaccine would offer them protection against those that are in the vaccine so yeah sure they should be vaccinated. Sounds good we get a lot of great influenza questions here's another one that we get typically I'll ask this one to Yabo. If a child younger than 36 months of age receives the appropriate volume dose 0.25 ccs of vaccine and then they age beyond that cutoff beyond the 36 month cutoff and if they happen to be a child that does require a second dose which which vaccine should they receive? Good question they should receive the age appropriate dose which in this case would be 0.5 ccs because now the child is over the age of three. Okay why don't we do one last quick question to Donna. We hear a lot about a lot of providers want us to recommend multiple doses for older patients so patients older than 65 which patients require two doses of influenza vaccine? Well two doses for adults is not recommended even though we know that sometimes they don't respond as well to the vaccine or that they may not have complete protection for a full year the data just doesn't indicate that giving a booster dose helps so the best thing to do really is you know you give the one dose and then you make sure that other people in the community are also vaccinated so that you've again got that good herd immunity and barrier of protection so the only ones really that need two doses are those young kids that are that are younger than nine years of age in their first influenza season or those unique scenarios that were that were mentioned earlier but no not for older people. Great thank you very much Donna and thank you Yavo. Meningococcal disease is an acute potentially severe illness caused by the bacterium nyserium meningitis. Nyserium meningitis is a leading cause of bacterial meningitis and sepsis in many parts of the world. Meningococcal disease is unique among causes of bacterial meningitis in that it causes not only sporadic disease but also outbreaks. In sub-Saharan Africa the organism causes major epidemics of meningitis in bacteremia. The world health organization estimated meningococcal disease was the cause of 171,000 deaths worldwide in 2000. Nyserium meningitis or meningococcus is an aerobic gram negative bacterium closely related to nyseria gonorrhea and to several non-pathogenic nyseria species. Meningococci are classified into groups called serogroups based on the characteristics of the polysaccharide capsule. At least 13 serogroups based upon the polysaccharide capsules have been described. However most invasive disease is caused by one of five serogroups A, B, C, Y, and W135. The relative importance of each serogroup depends on geographic location as well as other factors such as age. For instance, serogroup A is a major cause of disease in sub-Saharan Africa but is rarely isolated in the United States. The incubation period of meningococcal disease is short three to four days with a range of two to ten days. Meningococcal disease can have a variety of manifestations. Meningitis is the most common presentation and represents about half of all reported cases of invasive meningococcal disease. Meningeal infection is similar to other forms of acute purulent meningitis with sudden onset of fever, headache, and stiff neck. Meningococcal sepsis or meningococcemia may occur without meningitis. This condition is characterized by abrupt onset of fever and a particular or purpuric rash often associated with hypotension, shock, acute adrenal hemorrhage, and multi-organ failure. Less common presentations of meningococcal disease include pneumonia, arthritis, otitis media, and epiglottitis. The case fatality rate of invasive disease is 9 to 12 percent even with appropriate antibiotic therapy and intensive medical care. The fatality rate of meningococcemia is up to 40 percent. Up to 20 percent of survivors have permanent sequela such as hearing loss, neurologic damage, or loss of a limb. Nicerium meningetitis is a human pathogen that occurs throughout the world. Humans are the only natural reservoir of meningococcus. Up to 10 percent of adolescents and adults are colonized with meningococcus at any given time, although most of these strains are not pathogenic. Transmission is by respiratory droplets. The disease occurs most commonly in late winter and early spring. Communicability is generally limited. Studies of households in which a case of meningococcal disease has occurred indicate only 3 to 4 percent of households had a secondary case. Prior to a routine vaccination program, meningococcal disease was relatively rare in the United States with 2 to 3,000 cases reported each year. A total of 1,245 cases were reported in 2005. This graph shows the age-specific incidence of meningococcal disease in 1998. The overall rate in the United States was about one case per 100,000 population, shown here in the pink line. The highest age-specific rate was among infants younger than one year of age. Incidents declined in early childhood, increased during adolescence and early adulthood, declined among older adults, and increased again among persons 65 years and older. Although incidence is relatively low, more cases occurred in persons 23 to 64 years of age than occurred in any other age group. Although not as high as rates among infants and young children, adolescents and young adults have rates of invasive disease higher than the overall U.S. rate. This graph shows the rates of meningococcal disease by single year of age from 11 to 30 years of age. The two lines represent rates from two separate surveillance systems that show basically the same trend. The overall U.S. rate of meningococcal disease is about one case per 100,000 population, shown in the pink line. In 11 to 30 year olds, the rate of disease begins to increase at 11 or 12 years of age. It peaks around the age of 18 or 19 years at two cases per 100,000, which is twice the overall U.S. rate. By age 21, incidence falls below the overall U.S. rate. We hope that an adolescent strategy for the meningococcal conjugate vaccine will eliminate this peak. Andrew? The proportion of disease caused by different serogroups has changed during the last 15 years. From 1988 to 1991, most cases of meningoccal disease in the United States were due to either serogroup C or B, and serogroup Y accounted for only 2% of cases. In 1996 through 2001, serogroup Y accounted for 21% of cases, but serogroups C and B accounting for 42% and 31% respectively. Serogroups A and W135 are rare causes of invasive disease in the U.S. The proportion of cases caused by each serogroup varies by age group. In 2001, about two-thirds of cases among infants younger than one year of age were caused by serogroup B, for which no vaccine is available in the United States. The distribution of disease by serogroup continues to change. Data from 2002 through 2004 indicate that the proportion of cases caused by serogroups Y and B have continued to increase, while those caused by serogroup C continue to decline. Individual risk factors for the development of meningoccal disease include deficiencies in the terminal complement pathway and functional or anatomic asplenia. Persons with HIV infection are probably at increased risk for meningoccal disease. Additional risk factors include smoking and passive exposure to smoke, upper respiratory tract infection and crowding. In the African meningitis belt, an area that extends from Ethiopia to Senegal, seasonal peaks of meningoccal disease occur with rates several times higher than in industrialized countries. In addition, epidemics occur every 8 to 12 years with attack rates of 500 to 1000 cases per 100,000 population. In the United States, more than 95 percent of cases of meningoccal disease are sporadic single cases. But the meningoccal disease sometimes occurs in small outbreaks, both in the community and among organizations such as schools. Outbreaks have occurred among college students and led to concerns that this group might be at increased risk for the disease. Meningoccal disease is a reportable condition. Information on age is collected, but information about college attendance is not routinely collected. These are data from a 2001 publication on meningoccal disease among college age persons. It shows incidence rates among various groups of 18 to 23 year olds in 1998 and 1999. The overall incidence among 18 to 23 year olds, including those who are not college students, was 1.4 cases per 100,000 population, not much different than the overall U.S. rate. Among college freshmen, the rate was slightly higher, 1.9 per 100,000. But among college freshmen who live in dormitories, the rate was 5.1 per 100,000, more than twice as high as for all freshmen. Three times the rate for persons of the same age who do not attend college. A case control study among college students with meningoccal disease found that being a freshman living in a dormitory, white race, radiator heat, and recent upper respiratory infection were also risk factors for the disease. Interestingly, attending a movie in the prior month reduced the risk. Bill? There are two meningoccal vaccines available in the United States. Meningococcal polysaccharide vaccine called Menomune has been available since 1978. Meningococcal conjugate vaccine, brand name Menactra, was licensed by the Food and Drug Administration in January 2005. Both vaccines are produced by Santa Fe Pasteur. Meningococcal polysaccharide vaccine, Menomune, which we'll refer to as MPSV, is a quadrivalent vaccine that contains the capsular polysaccharide of meningococcal serogroups A, C, Y, and W135. Serogroups C and Y account for about two-thirds of disease in the United States. Serogroups A and W135 are rare in the U.S. MPSV is approved for persons two years of age and older, and MPSV is administered by the subcutaneous route. Meningococcal polysaccharide is a T cell independent antigen, like other capsular polysaccharides. As a result, meningococcal polysaccharide vaccine is less effective in children younger than 18 months of age than among older persons. It also does not produce good immunologic memory, and the antibody that's produced is not as effective as that produced by protein antigens. A protein conjugate meningococcal vaccine was finally licensed in 2005. The meningococcal conjugate vaccine, or MCV, is called Menactra. Like meningococcal polysaccharide vaccine, it's quite prevalent and contains the same serogroups as menomune, A, C, Y, and W135. The polysaccharides are conjugated to diphtheria toxoid. MCV was originally approved for persons 11 through 55 years of age, but in 2007, the Food and Drug Administration approved an expansion of the age range, and MCV is now approved for persons two through 55 years of age. MCV is administered by the intramuscular route. This is an important point. Meningococcal conjugate vaccine is administered by intramuscular injection, not by subcutaneous injection, like the polysaccharide vaccine. We've gotten a lot of questions about management of persons who received MCV by the incorrect route. There are a few data on the subcutaneous administration of meningococcal conjugate vaccine, so please be sure that you and your staff understand this and administer Menactra by the correct route. Meningococcal conjugate vaccine is supplied as a liquid in a single-dose vial. The stopper of the vial contains dry natural rubber latex. The vaccine does not contain a preservative. Meningococcal conjugate vaccine was not licensed based upon a clinical trial of vaccine efficacy as is typically done for new products. Rather, the efficacy of MCV was inferred by demonstrating that the serologic response to the vaccine was not inferior to the currently licensed polysaccharide vaccine. A similar or higher percentage of persons who received MCV had a significant increase in antibody level and similar often higher final tighter of antibody than those of similar age received the older polysaccharide vaccine. Donna. In the United States there are two meningococcal vaccines and recommendations for their use differ. Meningococcal polysaccharide vaccine is not recommended for routine vaccination of civilians in the United States. MPSV should be used only for persons at increased risk of infection who are 56 years of age or older or if MCV is not available. Use of meningococcal conjugate vaccine is preferred for persons two through 55 years of age for whom meningococcal vaccine is recommended. This preference is based on the immunogenicity of MCV demonstrated in pre-licensure studies. In addition, conjugate vaccines generate a stronger longer lasting immune response than the corresponding pure polysaccharide vaccine. With the availability of MCV, in 2005 the ACIP expanded its recommendations for the use of meningococcal vaccine in the United States. Meningococcal vaccine is routinely recommended for some children in the United States. Meningococcal conjugate vaccine is recommended for all children 11 or 12 years of age. The ACIP also recommends MCV for children 13 through 18 years of age if they have not been previously vaccinated. Unvaccinated college freshmen living in a dormitory should be routinely vaccinated. In addition, other persons two through 55 years of age who are at increased risk of invasive meningococcal disease should be vaccinated. The ACIP does not recommend routine meningococcal vaccination for children two through 10 years of age. However, children two through 10 years of age should be vaccinated if they are at increased risk of invasive meningococcal disease. For persons of any age, increased risk of meningococcal disease can result from an underlying medical condition or because of an exposure factor. Here are the medical conditions that increase the risk of meningococcal disease. Meningococcal vaccine is recommended for persons with terminal complement component deficiency which is a type of immunodeficiency disease as well as persons with HIV infection and functional or anatomic asplenia. Here are the groups that increase risk of exposure who should be vaccinated. These groups include military recruits and certain research and laboratory personnel, particularly those who are exposed routinely to meningococci in solutions that may be aerosolized. Vaccine is also recommended for travelers to and U.S. citizens residing in countries in which Nigeria meningeditus is hyperendemic or epidemic such as the Central African meningitis belt and Saudi Arabia. For all these groups, MCV is preferred if the person is two through 55 years of age. MPSV should be used for persons 56 years in older or if MCV is not available. Andrew? We receive many questions about revaccination with meningococcal vaccine. The questions are most often in the context of international travel or persons with the medical condition that increase the risk of meningococcal disease such as asplenia. Although there are limited data, revaccination may be indicated for persons who received MPSV and continue to be at increased risk for infection. For these persons revaccination may be considered five years after receipt of MPSV. The interval to revaccination may be shorter for children first vaccinated when they were younger than four years of age. Meningococcal conjugate vaccine is recommended for revaccination of persons two through 55 years of age who received MPSV. Revaccination after receipt of MCV is not recommended at this time. We expect that MCV will provide longer protection than the polysaccharide vaccine. However, studies will be needed to confirm this. We anticipate that more data will become available within the next five years to guide recommendations on revaccination for persons who were previously vaccinated with meningococcal conjugate vaccine. Contraindications and precautions for meningococcal vaccine are the same as those for most other inactivated vaccines. A severe allergic reaction to a vaccine component or following a prior dose is a contraindication to receipt of further doses. A moderate or severe acute illness is a reason to defer routine vaccination. Immunosuppression is not a contraindication to vaccination although the response to the vaccine may be suboptimal. Pregnancy is also not a contraindication to either meningococcal vaccine. Adverse reactions following meningococcal vaccines are similar to those following other inactivated vaccines and are generally mild. Data from the immunogenicity trials indicates that adverse reactions are more common following conjugate vaccine than polysaccharide vaccine. In persons 11 through 18 years of age, the most frequent adverse reactions following both types of vaccine are local reactions such as erythema and pain at the site of injection. These reactions last one or two days and occur in 3 to 29 percent of polysaccharide vaccine recipients and 11 to 59 percent of conjugate vaccine recipients. Low-grade fever was reported in 3 percent of polysaccharide vaccine recipients and 5 percent of conjugate vaccine recipients. Nonspecific systemic reactions such as headache, malaise and fatigue were reported in 8 to 29 percent of MPSV recipients and 11 to 36 percent of MCV recipients. Distribution of MCV began in January 2005. By mid-2005 cases of Guillain-Barre syndrome or GBS occurring among recipients of MCV began to be received by the vaccine adverse event reporting system or VAERS. As of December 31st, 2008, 37 cases of GBS have been reported and confirmed with onset within six weeks of MCV vaccination. 33 of these were persons 11 to 19 years of age. GBS is a rare illness and expected background incidence rates are not precisely known but the number of reports is similar to the number of cases expected to occur in this age group. The available data cannot determine with certainty if MCV increases the risk for GBS. As a result, no change in vaccine recommendations have been made at this time. CDC now recommends that persons with a history of GBS not receive MCV. However, persons with a history of GBS who are at especially high prolonged risk for meningococcal disease such as certain microbiologists might consider vaccination. Meningococcal conjugate vaccine is a valuable addition to our public health prevention program, particularly for adolescents and young adults. Links to the meningococcal ACIP statement revised recommendations for use of MCV vaccine among children two through ten years of age and other materials are on our updates and resources web page. In June 2006, the Food and Drug Administration approved the license application for the world's first vaccine against cervical and other analgenital cancers. The vaccine produces immunity to human papillomavirus or HPV. In this segment, we want to give you an overview of human papillomavirus, its epidemiology and disease burden and background for the new vaccine. We will then summarize the ACIP recommendations for use of the HPV vaccine. Human papillomavirus is the most common sexually transmitted infection in the United States with millions of new infections every year. Although most infections resolve spontaneously, in a small proportion of people the infection becomes chronic and can lead to serious disease years later. We asked Dr. Mona Soraya, a medical epidemiologist in the CDC Division of Cancer Prevention and Control, to tell us about human papillomavirus, its natural history and its relation to cancer. Human papillomavirus or HPV is a complex group of DNA tumor viruses and is the most common sexually transmitted infection in the United States. HPV infection can be completely asymptomatic and resolve spontaneously or can persist in the infected person and lead to a variety of medical conditions. There are more than a hundred different HPV types. More than 60 of these are characterized as cutaneous types and can lead to skin warts. About 40 types infect the epithelium of the mucosa, mainly the genital mucosa. The mucosal types are further categorized as high-risk types or low-risk types based on their ability to cause cancer. High-risk types, particularly type 16 and 18, are associated with cervical cell abnormalities and with certain anal genital cancers. Low-risk types, notably type 6 and 11, can also cause cervical cell abnormalities that usually resolve spontaneously and do not lead to cancer. Low-risk types can also cause genital warts and a rare condition called recurrent respiratory papillomatosis, a condition in which warts grow in the respiratory tract. It is estimated that more than 6 million new infections with HPV occur every year in the United States and about 20 million people, 15 percent of the U.S. population, are currently infected. Infection with one type of HPV does not prevent infection with another type. 5 to 30 percent of people infected with mucosal HPV are infected with multiple types of the virus. Initial HPV infection occurs soon after sexual initiation and approximately 70 percent of new infections resolve spontaneously within one year and more than 90 percent clear within two years. However, a small percentage of infections become chronic or persistent. It is these persistent infections that can lead to serious illness years or decades later. This graphic shows the natural history of HPV infection, the most common clinical significant manifestation of persistent genital HPV infection is cervical intraepithelial neoplasia or CIN. Within a few years of infection, low-grade CIN called CIN1 may develop, which may spontaneously resolve and the infection clear. Persistent HPV infection may progress directly to high-grade CIN called CIN2 or CIN3. High-grade abnormalities are at risk of progression to cancer and so are considered cancer precursors. A small proportion of high-grade abnormalities spontaneously regress. If left undetected and untreated, years or decades later CIN2 or CIN3 can progress to cervical cancer. In the U.S. effective cervical cancer screening programs are able to detect disease caused by HPV early when it is usually treatable. Persistent HPV infection can lead to cervical cancer years after the initial infection. HPV is believed to be responsible for nearly all of the 12,000 cases of cervical cancer diagnosed each year in the United States. In addition to cervical cancer, other cancers can be attributed to HPV infection as well. This graphic shows the number of cases of select cancers in the U.S. in 2002 and the fraction attributed to HPV types. As I mentioned earlier, among the 12,000 cervical cancers 100% are attributable to HPV. Of the 3,700 anal cancers 90% are attributable to HPV. Of the 4,480 vulvar or vaginal cancers and about 1,000 penile cancers 40% are caused by HPV. Finally, among 10,000 oral and pharyngeal cancers 12% are attributable to HPV. It is clear that human papillomavirus is responsible for a large proportion of the cervical and other analgenital cancers that occur in the United States. However, although there are more than 40 different types of HPV that infect the mucosa, much of this disease burden is caused by only a few types. This graphic shows the proportion of HPV related disease caused by just four HPV types, 16 and 18, which are considered to be high risk types, and 6 and 11 considered to be low risk types. This information is important because these four HPV types are included in the new quadrivalent HPV vaccine. HPV is associated with virtually all cervical cancers and type 16 and 18 are associated with 70% of these cancers. HPV type 16 alone is found in about half of all women with cervical cancer. High risk HPV type 16 and 18 are also associated with 30 to 50% of high and low grade cervical abnormalities and also with the proportion of anal, vulvar, vaginal and penile cancers. In addition, approximately 10% of head and neck cancers are attributed to HPV 16 and 18. Low risk type 6 and 11 are associated with about 10% of low grade cervical abnormalities, but 90% of genital warts and 90% of recurrent respiratory papillomatosis. The American Cancer Society estimates that in 2006 about 9,700 new cases of cervical cancer will be diagnosed in the United States. Approximately 3,700 women will die as a result of cervical cancer. Deaths will also occur as a result of other anal genital cancers. About $4 billion will be spent this year on management of sequelae of HPV infections primarily for the management of abnormal cervical cytology and treatment of cervical neoplasia. Disease caused by human papillomavirus is responsible for an enormous amount of suffering, death and medical cost in the United States. The burden of disease is even higher in developing countries where cervical cancer screening programs are inadequate or non-existent. Properly used HPV vaccine has the potential to reduce this burden of disease and save many lives both in this country and throughout the world. The vaccine approved by the Food and Drug Administration in 2006 is called Gardasil and is produced by Merck. The vaccine contains the outer protein called the L1 protein from four types of HPV, types 16 and 18 considered to be high-risk types and types 6 and 11 considered to be low-risk types. Production of the L1 proteins uses recombinant DNA technology similar to what is used for hepatitis B vaccine. The L1 proteins self-assemble into non-infectious units called virus-like particles or VLPs. VLPs are empty protein shells without genetic material. However, they are highly immunogenic and can induce high titers of neutralizing antibody. The vaccine is supplied as a liquid in a single-dose vial or syringe. The vaccine does not contain either antibiotic or preservative. HPV vaccine is intended to prevent cancer, primarily cervical cancer. But cancer can take decades to develop following HPV infection, so a clinical trial using cancer as the outcome is not very practical. Instead, other endpoints were used to determine vaccine efficacy, such as persistent HPV infection, genital warts, and cervical intraepithelial neoplasia, or CIN, which is considered a cancer precursor. Four efficacy and safety trials were conducted that included more than 16,000 females 16 through 26 years of age. Half of these participants, more than 8,000 women, received the vaccine. The other half received the placebo. The vaccine was found to be highly effective. This graphic shows clinical efficacy among women with no evidence of prior or current infection with vaccine HPV types. For prevention of HPV 16 or 18 related cervical intraepithelial neoplasia 2 or 3, or adenocarcinoma in situ, shown here as AIS, there were no cases among vaccine recipients compared with 53 cases among women who received placebo for a 100% efficacy. For prevention of any CIN or AIS, there were four cases among women who received vaccine and 83 in women who received placebo for an efficacy of 95%. For prevention of genital warts, there was one case in the vaccine group and 91 cases in the placebo group for an efficacy of 99%. Some women enrolled in the vaccine trials had evidence of past or current infection with HPV types included in the vaccine or abnormal PAP tests. There was no evidence that the vaccine had efficacy against existing disease or infection, that is the vaccine had no therapeutic effect. However, prior infection with one HPV type did not diminish efficacy of the vaccine against other vaccine HPV types. Female participants in the clinical trials were grouped by age. Clinical efficacy was studied in 16 through 26 year olds. 9 through 15 year olds were also enrolled to study immunogenicity and safety of the vaccine. The younger group was not followed with PAP tests. The antibody response to the vaccine among the 9 through 15 year olds was compared to the antibody response in 16 through 26 year olds in whom clinical protection was determined. The younger participants responded to the vaccine with even higher antibody titers than the older group so clinical protection was inferred in the younger group. Males were included in the immunogenicity studies but efficacy data in males are not yet available. Additional studies are in progress now including efficacy studies in males and efficacy studies in females older than 26 years. Long-term follow-up studies are underway to look at the duration of protection. Data from these studies will be available in the next few years. HPV vaccine is currently approved by the Food and Drug Administration for females 9 through 26 years of age. The vaccine is not approved for males of any age at this time and should not be administered to females younger than 9 or older than 26 years. Merck has applied to the Food and Drug Administration for a labeling change to include women older than 26 years but this has not happened yet so for now only females 9 through 26 years should be vaccinated. The routine schedule is three doses at zero, two and six months. ACIP included information on minimum intervals between doses in its 2006 HPV statement. However, minimum intervals between doses should not be used for routine HPV vaccination. There are almost no situations where a compressed or accelerated schedule is needed. One additional HPV vaccine interval issue ACIP has not defined a maximum interval between HPV vaccine doses. If the interval between doses is longer than recommended you should just continue the series where it was interrupted. It is not necessary to add doses or restart the series because of an extended interval between doses. Remember that the minimum intervals between doses should not be used for routine vaccination. There are data that indicate very high efficacy when the three-dose HPV series is administered during a six-month period and it is at this dosing schedule that you should be using. More information about the clinical trials that led to the licensure of the vaccine is available in the package insert and in the ACIP statement. Dana? The ACIP recommendations for use of human papillomavirus vaccine were published in March 2007 but before we talk about the vaccine recommendations I am required by federal law to tell you this. Correct and consistent condom use may have a protective effect on HPV acquisition, reduce the risk for HPV associated diseases, and mitigate the adverse consequences of infection with HPV. The ACIP recommends routine vaccination of females 11 or 12 years of age with the three-dose series. This age corresponds to that of other recent recommendations for acellular pertussis and meningococcal conjugate vaccines. The vaccination series can be started as young as nine years of age at the clinician's discretion. While the recommended age for routine vaccination is 11 or 12 years there will be older females who could benefit from the vaccine. Vaccination is also recommended for females 13 through 26 years of age who have not been previously vaccinated. Vaccine should be administered before onset of sexual activity if possible but females who are sexually active should still be vaccinated. In this age group females not yet sexually active can be expected to have the full benefit of vaccination because they are not infected with HPV. Sexually active females may not have full benefit of the vaccine because they may have been already infected with vaccine HPV types. However only a small percentage of sexually active females are likely to have been infected with all four HPV vaccine types. For those already infected with one or more vaccine HPV types the vaccine would provide protection against disease caused by the other vaccine HPV types. So although overall vaccine effectiveness would be lower when administered to a population of females who are sexually active most females will still derive some benefit from vaccination. There are a variety of what ACIP calls special situations for HPV vaccine. Vaccine can be administered to females 26 years of age or younger with an equivocal or abnormal PAP test, a positive HPV DNA test meaning they are currently infected or those with genital warts. However these women should be informed that the vaccine will have no effect on existing disease or infection. Females 26 years of age or younger who are lactating and breastfeeding or who are immunocompromised may be vaccinated. However the vaccine is not recommended for pregnant women. Although HPV is an inactivated subunit vaccine ACIP prefers a conservative approach to the vaccination of pregnant women. Initiation of the vaccine series should be delayed until after completion of the pregnancy. If a woman is found to be pregnant after initiating the vaccination series completion of the series should be delayed until after the pregnancy. If a vaccine dose has been administered during pregnancy there is no indication for intervention. A vaccine in pregnancy registry has been established and women vaccinated during pregnancy should be reported. The telephone number is in the vaccine package insert. Yabba? HPV vaccine has a limited number of contraindications and precautions. As with all vaccines HPV vaccine should not be administered to persons with a history of a severe allergic reaction to a vaccine component or following a prior dose. Vaccination of persons with moderate or severe acute illness should be deferred until the acute illness improves. Adverse reactions following HPV vaccine are similar to most other inactivated vaccines. In the pre-licensure clinical trials local reactions such as pain, redness or swelling were reported in 25 to 84 percent of recipients. A temperature of 100 degrees fahrenheit in the 15 days after vaccination was reported in 10 percent of vaccine recipients. A similar proportion of placebo recipients reported a temperature. No serious adverse events have been associated with HPV vaccine. Local reactions increased in frequency with increasing doses. However reports of fever did not increase significantly with increasing doses. The vaccine adverse event reporting system is being carefully monitored for HPV vaccine reports like it is for all new vaccines. Fares has detected an increase in the number of reports of syncope following vaccination. Many of these events have followed administration of HPV vaccine. Providers need to be aware that syncope can occur after vaccination and may be more common among adolescents and young adults. Be sure to have the person sit down when being vaccinated. You should also consider a 15 to 20 minute observation period after vaccination as discussed in the 2006 general recommendations on immunization. HPV vaccine is a major breakthrough in public health but it's not the final solution to cervical cancer prevention. The vaccine HPV types are responsible for about 70 percent of cervical cancers so cervical and other cancers will continue to occur among vaccinated women because of the 30 percent of oncogenic HPV types not included in the vaccine. That is why continued cervical cancer screening is critical. Cervical cancer screening recommendations have not changed for females who receive HPV vaccine. HPV types in the vaccine are responsible for about 70 percent of cervical cancers. Females who are vaccinated could subsequently be infected with a carcinogenic HPV type not in the quadrivalent vaccine. Also females who are sexually active prize of vaccination could have been infected with a vaccine type HPV before vaccination. Healthcare providers who are administering HPV vaccine should take the opportunity to educate women about the importance of cervical cancer screening at intervals recommended by national organizations. Gardasil is packaged in single-dose vials and syringes. It should be stored in the refrigerator with other inactivated vaccines. However, it is sensitive to light which we usually associate with live vaccines. Be sure to keep the vials or syringes in the original boxes with the tops closed until ready for use. The vaccine should be used promptly after removal from the refrigerator. The availability of a vaccine to prevent human papillomavirus and the sequelae of persistent infection is a major advance in preventive medicine. We look forward to complete implementation of this new vaccine and the improvement in women's health that will accompany it. Thank you Yabo. We receive a lot of questions from providers about HPV vaccine and I guess I'll go through some of them right now. I'll pose the first question to Donna. It has to do with minimum intervals. Providers have used minimum intervals in the past and I think with this vaccine in particular are there any instances where it's really justified? Well I mean I think if you know there was a risk that you weren't going to be able to get all three doses in and maybe somebody was going to be traveling and gone for a long time you know it might be something like that but just for convenience to try to scrunch them together and get them in we really do not recommend that at all. And remember that if you are concerned that someone is going to age out and not finish the series say you start vaccinating someone who's 26 and they're going to turn 27 before you finish the series you can you can finish it that's okay. What's not recommended is to start the series at 27 not at this time because it's not approved you know beyond 26 but you can finish a series at 27 that you've started and um and you don't you know there I think there also was some concern that if they didn't get all the doses in you know quickly that you would end up going too long and have to start the series over and that's not true you know there there's no maximum intervals you don't have to restart the series you would just pick up where you left off and finish it. So try as much as possible to stick as closely to those those recommended intervals in that six-month time frame because that's where the best data is on getting the results that we want with this vaccine. Excellent I think another point that just to make again providers are asked HPV vaccine only recommended up through 26 years why is that exactly why we cut it off there a lot of providers are really interested in knowing more about that. Right Andrew and really this is similar to other vaccines as well why is it that they are only recommended for certain ages well it's really based on the pre-licensure studies and the ages of the groups that are studied and as Donna already mentioned with HPV vaccine if someone were to start this even though it was only licensed till 26 years old if someone were to start the series at 26 and didn't finish they could complete it after the age of 26. So really this is the concerns. Thank you very much Yabo. Thank you Donna. This brings us to the close of this session of epidemiology and prevention of vaccine preventable diseases. We would like to remind you of resources that you can use to get more information or to contact us. Here's the companion book for this program. The public health foundation is the sole source for a printed copy. The book costs $35 plus shipping and handling and is a useful resource for any office that administers vaccine to persons of any age. You can contact the public health foundation through their toll-free number at 877-252-1200. You can also order materials online from their website at bookstore.phf.org. If your patients or their parents have immunization related questions you can refer them to the CDC Info Contact Center. You can reach the contact center toll free at 800 CDC Info. The CDC Info Contact Center is staffed 24 hours a day seven days a week. If you or your staff have questions you should direct them to us at the National Center for Immunization and Respiratory Diseases by email. Our email address is nipinfo.cdc.gov Throughout this program we've mentioned additional immunization resources available to you on the updates and resources web page. The address is www.cdc.gov front slash vaccines. Click on education and training then the self-study link. Choose this program from the list to find all the materials we've discussed during this program. We want you to have the most current immunization information at your fingertips. An easy way to do this is to have the information available on your computer. We've compiled all the current ACIP statements, vaccine information statements, the course text, and much more on a CD called Immunization Works. The CD is a great way to have all your current immunization information together in one place. Immunization Works is distributed free of charge by the CDC. The updates and resources web page has a link to order it. Continuing education credit is available for viewing this program. Details and instructions can be found in the continuing education chapter of the DVD or on the updates and resources web page. Thank you for joining us for this session of Epidemiology and Prevention of Vaccine Preventable Diseases. Please join us for other programs in this series when we discuss specific vaccine preventable diseases and the vaccines to prevent them. Until then, goodbye.