2009 Influenza A(H1N1) Monovalent Vaccines for Children

THE 2009 INFLUENZA A(H1N1) VIRUS WAS FIRST IDENtified 8 months ago, but the virus has already had a substantial effect on human health. Influenza activity in the United States has remained higher than normal since May, and measures of severe illness such as hospitalizations and deaths during the summer and fall have been equal to or higher than rates usually observed in a typical winter influenzaseasoninallagegroupsexceptolderadults.Eventhough influenzaactivityhasdecreased inrecentweeks insomestates, there remains thepossibilityof continuedactivity through the traditionalwinter influenzaseasonandtheprospectofnormal winter circulation of seasonal influenza viruses. The 2009 influenza A(H1N1) pandemic highlights the role of children in influenzaepidemiology.Serological studies suggestedthatchildrenhadnomeasurableimmunityagainstH1N1 prior to the outbreak. In addition, children have been a primary source of illness in community outbreaks of pandemic influenza, as indicated by the association between outbreaks inschoolsor summercampsand influenzaactivity in thecommunity. Children also have developed severe influenza A(H1N1)–related complications more frequently than is usually seen for seasonal influenza and reports of pediatric deaths and hospitalizations continue to increase. As of December 5, 2009,224laboratory-confirmeddeathsamongchildrenhadbeen reported to theCenters forDiseaseControlandPrevention, far surpassing any recent influenza season, and the actual numberofpediatricdeathsduetothe influenzaA(H1N1)viruspandemic is likely to be considerably higher. Children have been among the primary groups targeted for the limited amount of vaccine available in most areas. A logistical challenge for immunization programs and clinicianswhoprovidevaccinationsistheneedfor2dosesinyoung children. For seasonal influenza vaccine, 2 doses are recommendedforallchildrenyoungerthan9yearswhoarebeingvaccinated for the first time, based on immunogenicity and vaccine effectiveness studies that indicate better protection with a 2-dose schedule for young children. For the 2009 influenza A(H1N1) monovalent vaccines, the current recommendation is based on these seasonal vaccine studies even though the age group recommended for 2 doses is children younger than 10 years. The report by Nolan and colleagues in this issue of JAMA indicates that a single 15-μg dose of an unadjuvanted inactivatedinfluenzaA(H1N1)vaccinecanelicitsignificant increases in influenza-specific antibody in more than 90% of healthy infants and young children. A second dose given 21 days later yielded significantly higher antibody levels. Data indicating that influenzaA(H1N1)vaccinesare immunogenicat licensed dosesandschedulesisexcellentnewsforchildren,parents,health care professionals, and public health workers who have participated inpediatric immunizationprograms.Alsoreassuring are the findings from the safety analyses reported by Nolan et al, which indicate that this unadjuvanated vaccine is well tolerated with a safety profile similar to the seasonal influenza vaccine—an expected result given that the pandemic vaccine manufacturingprocess is identical tothatusedforseasonalvaccines. Although the finding that a single dose is immunogenic in mostyoungchildren is encouraging, it ispremature toassume that only 1 dose will be needed to provide adequate protection for all young children based on these data. Rather, the results fromthisstudymustbeconsideredinthecontextofpriorstudies ofseasonalvaccineimmunogenicityandeffectivenessinchildren. Thehemagglutination inhibition(HI) testused in the study by Nolan et al is the primary accepted measure of influenza immunogenicity.The testmeasureshowwell antibodies inserum from vaccinated (or previously infected) persons are able to compete with animal-derived red blood cells in binding influenzaviruses.Theabilityofseratoinhibitbindingbyredblood cellsathigherdilutionsindicatesahigheramountofvirus-specific antibody in the specimen. An HI titer of 1:40 or greater in Nolan et al and in most other studies is understood to represent the levelatwhichapproximately50%of individualswillbeprotected after receiving a seasonal influenza vaccine; and higher levelsof antibodygenerallycorrelatewithgreaterprotection. The evidence that led to the 2-dose recommendation for vaccine-naivechildrenreceivingseasonal influenzavaccinewas based on immunogenicity data and has been supported by effectivenessdata. Infantsandyoungchildrennotpreviouslyvaccinated with seasonal vaccine have a lower immune response to1doseofvaccinecomparedwitholderchildrenandadults. Basedonthe immunogenicitydataalone,apossibleconclusion is thatonly1doseof the2009 influenzaA(H1N1)vaccineprovides protection to a substantial proportion of previously unvaccinated children in some seasons. However, studies of vaccineeffectivenesshaveconsistentlydemonstrated that2doses of seasonal influenza vaccine provide better protection than 1