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The expansion of the immunization schedule for 2009 has resulted in several success stories. Two rotavirus vaccines are now available. Following the introduction of immunization against rotavirus, a sharp decline in cases of rotavirus gastroenteritis was seen.
Rotavirus vaccines. Rotavirus has been the most common cause of severe gastroenteritis in pediatric patients. In the United States, rotavirus gastroenteritis accounts for 55,000 to 70,000 admissions, approximately 250,000 emergency department visits, and many more office visits annually.1 Worldwide, rotavirus has been responsible for about 500,000 deaths each year. Virtually all children become infected by age 5 years, and many experience repeat infections with rotavirus before age 5. Given this epidemiology, there has been an appreciable economic as well as social burden. Although the gastroenteritis caused by rotavirus is usually associated with diarrhea, vomiting, and fever, it may occur without diarrhea. Thus, the disease may actually be underrecognized.
Two new rotavirus vaccines have been approved for use in the past 3 years. RV5 (RotaTeq) is a reassortant human-bovine pentavalent vaccine that was approved by the FDA in February 2006. RV1 (Rotarix) is a human monovalent vaccine that was approved in April 2008. Three doses of RV5 are recommended, to be given at ages 2, 4, and 6 months. The first dose should be given at age 6 to 12 weeks, and there should be an interval of 4 to 10 weeks between doses. The series should be completed by age 32 weeks. Two doses of RV1 are recommended, to be given at ages 2 and 4 months. The first dose can be given as early as age 6 weeks; there should be at least 4 weeks between the first and second dose. The series should be completed by age 24 weeks.
In 1998, a rhesus-based tetravalent rotavirus vaccine (RotaShield) was approved for use in the United States. Within 1 year of launch, however, this vaccine was withdrawn because of its association with intussusception. Concern for intussusception necessitated large-scale trials before approval of RV5 and RV1. Fortunately, no evidence of intussusception has been seen with the 2 new vaccines. Both RV1 and RV5 are given orally and are well tolerated in general. However, because of the experience with RotaShield, the dosing schedules were developed cautiously and administration was required early in the first year of life, thereby avoiding the age when intussusception is most likely to occur.
The CDC recently published their recommendations for the use of RV1 and RV5 (Table).1 They sought to harmonize the schedules of the 2 products; thus, their schedule is somewhat more flexible than the schedules of the FDA, which appear on the product labels (and which are described above). In general, whenever possible, it seems prudent to adhere to product labeling instructions. A harmonized schedule similar to that recommended by the CDC is also available from the American Academy of Pediatrics.2
Prospective population-based surveillance studies have been conducted for children younger than 3 years in 3 US counties.3 Rotavirus activity during the 2007-2008 season was compared with activity from 1991 to 2006. RV5 was the only rotavirus vaccine available during the time this study was conducted; mean coverage among infants aged 3 months was only 49% in May 2007 and 56% in March 2008. Despite these modest coverage levels, only 6% of fecal specimens were positive for rotavirus, compared with positive test rates of more than 50% in the previous 2 seasons. In addition, rotavirus activity in the 2007-2008 season appeared to have been delayed in onset by 2 to 4 months and diminished in magnitude by more than 50% compared with the previous several seasons. These results exceeded expectations and suggest that appreciable herd immunity is a real possibility.
New combination vaccines. The rapid development of new vaccines over the past 2 decades has meant more injections. Parents frequently object to their children receiving 4 or more separate injections at a single visit and, consequently, often request deferral of some of the injections. This results in periods of susceptibility and ultimately may reduce successful completion of the vaccine series. Combination vaccines can help improve the timeliness of immunizations.
The diphtheria-tetanus–acellular pertussis (DTaP)–inactivated polio (IPV)–hepatitis B combination vaccine (Pediarix) has been available for several years. Now, DTaP-IPV in combination with conjugate Haemophilus influenzae type b (Pentacel) has been approved for use in the United States. Pediarix, if used for all 3 recommended doses (at ages 2, 4, and 6 months), may result in a fourth, or extra, dose of hepatitis B vaccine in infants who received a birth dose of monovalent hepatitis B vaccine; this is not harmful. Pentacel can be used to provide a fourth dose of polio vaccine at the 18-month visit. However, when 4 doses of IPV are administered before a child's fourth birthday, an additional dose of age-appropriate IPV must be given after the fourth birthday.
The reason it took so long to develop such a combination vaccine is that combining DTaP with H influenzae type b has been known to potentially result in interference, ie, the lowering of levels of antibody to an antigen-in this case, antibody to the Haemophilus capsule. Such antibodies serve as the marker for protection. Interference was seen with previous products that had been developed. In addition, because there is no adequate serological surrogate for prediction of protection against pertussis, carefully designed studies must be conducted to provide sufficient confidence that the new vaccine is effective. Before its approval by the FDA, Pentacel had to be evaluated with regard to these 2 issues. Since 1997, Pentacel has been the only vaccine of this type that has been used in Canada. With approximately 14,000,000 doses administered, no increase in cases of invasive H influenzae type b disease or pertussis has been seen. In addition, levels of antibody to the capsule of H influenzae type b and antibody to pertussis antigens seen with Pentacel have been found to be comparable to levels seen with individual-component vaccines (ie, DPT, IPV, and H influenzae type b). These results provide reassurance that comparable efficacy can be anticipated when this combination vaccine is used.
Influenza. The very young, the elderly, and those with certain underlying health problems are traditionally at greatest risk for influenza. School-aged children, however, generally serve as the vectors and transmit the infection to those persons at highest risk. A change in the influenza immunization strategy has recently been endorsed with this in mind. There are actually several reasons for this change. First, identifying high-risk patients is difficult, and even after such persons are identified, adherence to influenza immunization has not been satisfactory. Second, vaccine efficacy is suboptimal in the elderly.4 Thus, immunization of high-risk adults will now be combined with immunization of all children between the ages of 6 months and 18 years. It is hoped that full implementation of this policy will be more effective at reducing influenza in the population as a whole,5 reducing the total number of annual influenza cases by 91% and cutting the number of influenza-related deaths from 28,000 to 5900.6
Two influenza vaccines are currently available for use. The killed influenza vaccine-trivalent inactivated vaccine (TIV)-is administered intramuscularly and accounts for the vast majority of doses used. A new formulation of the live attenuated influenza vaccine (LAIV; FluMist) has an expanded indication. LAIV can now be used in patients aged 2 to 49 years. It should not be used in patients younger than 5 years with recurrent wheezing or in any patients known to be asthmatic. Some trials have suggested that LAIV has better efficacy than the injectable vaccine, TIV, in those years when the circulating influenza strain fails to match the vaccine strain.7 With such a sharp and sudden increase in the number of persons for whom immunization is now indicated, school-based programs are being considered. LAIV would seem to be well suited for this application.
CHALLENGESVaccine refusal and under-immunization. Not in spite of, but perhaps in part because of, recent successes, new challenges have emerged on the immunization front. As vaccine-preventable diseases have disappeared, and as the immunization schedule has expanded, vaccine refusal has increased. Estimated coverage of pediatric patients for the standard vaccination schedule has dropped to 72%.8 Measles activity is widespread in Europe, and numerous outbreaks were reported in 2008 in the United States. Five cases of invasive H influenzae type b disease were recently reported in Minnesota.9 Five additional cases, including 2 deaths, have also been reported in the Philadelphia area. Vaccine refusal has played a role in these situations.
In addition to those parents who refuse to vaccinate their children altogether, others request alternative schedules. Of these, "Dr Bob's Alternative Vaccine Schedule" is one of the most widely recognized. Such "designer schedules" generally lead to vaccines being delayed or missed altogether. For example, Dr Bob's Alternative Schedule recommends giving single doses of measles, mumps, and rubella vaccines as opposed to the combination measles-mumps-rubella vaccine. Such a policy serves to greatly increase the cost of vaccination, the number of visits required to immunize, and the time during which the patient is at risk for or susceptible to the diseases involved.
For an extended discussion of vaccine refusal and vaccine safety, see "Point-Counterpoint: Responding to Common Reasons for Vaccine Refusal," by Ahdi Amer, MD.
Breakthrough disease. Not all the problems of breakthrough disease are the result of vaccine refusal. More cases of invasive disease caused by Streptococcus pneumoniae are being reported in fully immunized children. These infections are generally caused by serotypes of
S pneumoniae that are not included in the 7-valent conjugate vaccine currently used (Prevnar). Many of these serotypes are highly resistant strains. However, plans for the inclusion of these strains in future 10- and 13-valent vaccines give reason for optimism that we can continue to hold on to gains seen in the prevention of invasive disease due to S pneumoniae. In addition, an expanded indication for a conjugate meningococcal vaccine, allowing its use in patients younger than 1 year, also seems feasible in the near future and would provide protection for those patients at highest risk.
Human papillomavirus (HPV) vaccine. Safety concerns have not been limited to vaccines used in infancy for the primary series. Potential safety concerns associated with the HPV vaccine have been the subject of intense scrutiny by the media and have likely been a factor in declining acceptance of this vaccine. Concerns regarding the HPV vaccine are discussed in "HPV Vaccine: Three Years Later," by Jean Someshwar, MD, and Naga Sirikonda, MD.
Vaccine shortages. Shortages of certain vaccines have occurred regularly during the past decade. Such shortages have forced providers to withhold doses and notify patients at a later date when supply is restored.
Which vaccines are in short supply? Currently, several vaccines are available in limited supply.10 The most notable examples are 2 of the conjugated H influenzae type b (Hib) vaccines (PedvaxHIB and Comvax), varicella vaccine products, and some hepatitis A and B vaccines. Beginning in December 2008, Merck notified the CDC that it no longer planned to manufacture the monovalent measles, rubella, or mumps vaccines.
The nationwide shortage of the Hib vaccines that began in December 2007 has been especially concerning, given the breakthrough disease. The shortage resulted from a recall of certain lots of the vaccine and the fact that Merck suspended production of its 2 Hib vaccines. In response to the shortage, the CDC recommended a temporary deferral of the booster dose of the conjugated Hib vaccine, usually administered between 12 and 15 months of age, for non–high-risk patients. However, supplies have improved, and the CDC has recommended reinstating the booster dose for children aged 12 to 15 months. Older children for whom the booster dose was deferred should be brought up to date at their next regularly scheduled visit. The recent history of breakthrough disease caused by Hib vaccine refusal, along with the shortage of the vaccine, makes completion of this series especially important.
The 2 manufacturers of the pediatric hepatitis B vaccines, Merck and GlaxoSmithKline, have experienced an inability to fill all orders for these vaccines. Consequently, the CDC has released doses from its stockpiles.
Varicella antigen for vaccine formulations is used in 3 products. This antigen is not available in quantities sufficient to supply all of these vaccines. Currently, the measles-mumps-rubella-varicella combination vaccine (Proquad) is not available. However, Varivax is available in sufficient quantities to meet the need for the 2-dose pediatric immunization series against varicella.10
Causes and consequences of shortages. Several issues contribute to vaccine shortages. The principal reason several manufacturers have exited this market is probably that the manufacture of vaccines provides lower profits and substantial liability compared with the manufacture of a drug that patients might take for the remainder of their lives. Vaccine shortages have further eroded public confidence in immunization recommendations, and deferring doses as necessitated by shortages can ultimately result in doses that are completely missed.
Economic issues impact not just manufacturers. More physicians are electing not to provide vaccines for patients in their office. The profit margins may be small relative to the cost of maintaining a significant inventory of vaccines. However, sending patients to public health facilities for immunizations runs counter to efforts to establish a medical home for all patients in America. In short, developing a comprehensive plan for funding and providing an adequate supply of vaccines is needed now more than ever.
Cortese MM, Parashar UD; Centers for Disease Control and Prevention. Prevention of rotavirus gastroenteritis among infants and children: recommendations of the Advisory Committee on Immunization Practices (ACIP).
MMWR Recomm Rep.
American Academy of Pediatrics. Prevention of rotavirus disease: updated guidelines for use of rotavirus vaccine. Committee on Infectious Diseases.
Centers for Disease Control and Prevention. Delayed onset and diminished magnitude of rotavirus activity-United States, November 2007-May 2008.
Weinberger B, Herndler-Brandstetter D, Schwanninger A, et al. Biology of immune responses to vaccines in elderly persons.
Clin Infect Dis.
Reichert TA, Sugaya N, Fedson DS, et al. The Japanese experience with vaccinating schoolchildren against influenza.
N Engl J Med.
Weycker D, Edelsberg J, Halloran ME, et al. Population-wide benefits of routine vaccination of children against influenza.
Belshe RB, Gruber WC, Mendelman PM, et al. Efficacy of vaccination with live attenuated, cold-adapted, trivalent, intranasal influenza virus vaccine against a variant (A/Sydney) not contained in the vaccine.
Luman ET, Shaw KM, Stokley SK. Compliance with vaccination recommendations for US children [published correction appears in
Am J Prev Med.
Am J Prev Med.
Centers for Disease Control and Prevention. Invasive
type b disease in five children-Minnesota, 2008.
. Centers for Disease Control and Prevention. Current Vaccine Shortages and Delays.
. Accessed September 24, 2009.