Key points

Introduction

Influenza, a common, highly contagious, acute, febrile respiratory disease, is caused by influenza virus, which circulates globally. Influenza virus causes annual outbreaks, with or without seasonality, which are likely related to climate and other factors that influence transmission. The influenza virus undergoes frequent antigenic mutations, known as antigenic drift, that contribute to variability from year to year and present challenges for annual vaccine design and production. In addition, influenza poses a unique potential to cause pandemics when a novel virus emerges through genetic reassortment, or antigenic shift, resulting in a virus with surface glycoproteins against which there is little preexisting immunity in the population.

Influenza virus affects people of all ages and causes mild to severe illness and even death in some cases. According to the World Health Organization (WHO), annual epidemics of influenza result in an estimated 3 to 5 million cases of severe illness and between 250,000 and 500,000 deaths worldwide, although the cocirculation of other pathogens and lack of diagnostic testing in many settings makes it difficult to accurately estimate the burden of influenza. As influenza is a vaccine-preventable illness, it is important from a global health standpoint to differentiate illnesses attributable to the influenza virus from influenza-like illnesses caused by other pathogens.

Those at increased risk for the most severe illness, or influenza-related complications, include the elderly, children younger than 5 years, and individuals of all ages, who are immunocompromised or have chronic underlying health conditions that predispose them to more severe disease, as well as pregnant women. Although health care workers are not at higher risk than the general population for influenza-related complications, they are a group that is often prioritized for vaccination to maintain the workforce and to prevent them from transmitting influenza to vulnerable patients.

Although treatment of influenza infection is available in certain settings, prevention is the better option. The best way to prevent influenza infection is by vaccination. Vaccination against influenza can prevent the primary influenza syndrome as well as complications, such as acute otitis media (AOM) or pneumonia.

This article focuses on pediatric influenza and gives an overview of the influenza virus as well as the epidemiology of the disease. It includes information on influenza in children in low-resource settings, where available, and a discussion of influenza vaccines, treatments, and policy recommendations.

Introduction

Influenza, a common, highly contagious, acute, febrile respiratory disease, is caused by influenza virus, which circulates globally. Influenza virus causes annual outbreaks, with or without seasonality, which are likely related to climate and other factors that influence transmission. The influenza virus undergoes frequent antigenic mutations, known as antigenic drift, that contribute to variability from year to year and present challenges for annual vaccine design and production. In addition, influenza poses a unique potential to cause pandemics when a novel virus emerges through genetic reassortment, or antigenic shift, resulting in a virus with surface glycoproteins against which there is little preexisting immunity in the population.

Influenza virus affects people of all ages and causes mild to severe illness and even death in some cases. According to the World Health Organization (WHO), annual epidemics of influenza result in an estimated 3 to 5 million cases of severe illness and between 250,000 and 500,000 deaths worldwide, although the cocirculation of other pathogens and lack of diagnostic testing in many settings makes it difficult to accurately estimate the burden of influenza. As influenza is a vaccine-preventable illness, it is important from a global health standpoint to differentiate illnesses attributable to the influenza virus from influenza-like illnesses caused by other pathogens.

Those at increased risk for the most severe illness, or influenza-related complications, include the elderly, children younger than 5 years, and individuals of all ages, who are immunocompromised or have chronic underlying health conditions that predispose them to more severe disease, as well as pregnant women. Although health care workers are not at higher risk than the general population for influenza-related complications, they are a group that is often prioritized for vaccination to maintain the workforce and to prevent them from transmitting influenza to vulnerable patients.

Although treatment of influenza infection is available in certain settings, prevention is the better option. The best way to prevent influenza infection is by vaccination. Vaccination against influenza can prevent the primary influenza syndrome as well as complications, such as acute otitis media (AOM) or pneumonia.

This article focuses on pediatric influenza and gives an overview of the influenza virus as well as the epidemiology of the disease. It includes information on influenza in children in low-resource settings, where available, and a discussion of influenza vaccines, treatments, and policy recommendations.

Influenza in children: clinical characteristics and disease burden

In otherwise healthy children, influenza is typically a mild to moderate disease and, in most children, resolves without complications. The most common signs and symptoms of influenza in children are sudden onset of fever, cough, and rhinorrhea. Influenza is most severe in younger children. Symptoms, such as sore throat, headache, myalgia, and fatigue, are reported less commonly in children than adults. This difference may be due in part to the inability of young children to describe these complaints. Because the signs and symptoms of influenza are not unique to this disease and the presentation of certain signs and symptoms varies among individuals, it can be difficult to diagnose influenza by clinical presentation alone; thus, a firm diagnosis generally requires laboratory confirmation.

Clinical attack rates and morbidity from influenza infection vary considerably from year to year and across geographies. When compared with adults, influenza attack rates are consistently higher in children and may reach 30% or more during selected seasons. Data from the United States show the importance of laboratory testing in fully understanding the burden of influenza illness. Among young children, few influenza infections are recognized by clinical signs and symptoms alone; in one population-based US study of children younger than 5 years, only 17% of outpatient and 28% of inpatient cases of laboratory-confirmed influenza (LCI) received a clinical diagnosis of influenza from their health care provider before laboratory results were known.

Although influenza-related hospitalization and death, discussed later, do occur, outpatient visits are far more common for all age groups. With increasing age, more children with influenza can be managed as outpatients, whereas with younger children, influenza tends to be more severe and more often requires hospitalization. In one population-based study in the United States, annual influenza-attributable outpatient visit rates were approximately 10-, 100-, and 250-fold greater than the rates of hospitalization for children younger than 5 months, 6 to 23 months, and 24 to 59 months, respectively. Antibiotic use also increases as a result of influenza infections. A retrospective cohort study of children younger than 15 years over 19 influenza seasons in the United States estimated that for every 100 children, an average of 6 to 15 outpatient visits and 3 to 9 courses of antibiotics were attributable to influenza every year.

LCI-related hospitalization rates are high among young children, ranging from 0.58 to 2.4 hospitalizations per 1000 children younger than 5 years per year in the United States. Children younger than 6 months consistently have high rates of hospitalization, and about 80% to 85% of pediatric influenza-attributable hospitalizations are accounted for by children younger than 24 months. Hospitalizations due to LCI are likely underestimated for several reasons, including lack of diagnostic testing, insensitive diagnostic methods, and influenza virus being in the causal pathway to the hospitalization but no longer present at time of testing (eg, influenza virus leading to bacterial pneumonia or asthma exacerbation).

Influenza infections can be complicated by other secondary infections, which add considerably to the burden of influenza. Clinically, AOM is the most frequent influenza-associated syndrome. Another significant, though less common, complication of influenza is pneumonia. Although pneumococcal and Haemophilus influenzae type B (Hib) infections were commonly identified pathogens preceding or concomitant to influenza infection in children, such secondary infections are less frequent now that pneumococcal and Hib vaccines are routinely administered to children. Hospitalized children with influenza-associated bacterial pneumonia are more likely to have a severe and complicated clinical course than those hospitalized for influenza without associated pneumonia. Influenza-associated pneumonia can be particularly dangerous in children with underlying conditions and can be fatal. In a mortality study in children hospitalized with LCI in the United States from 2004 to 2007, Staphylococcus aureus was the most common bacterial infection identified in children with influenza.

Although death due to influenza is rare in an individual child, the annual outbreaks and high attack rates of the disease lead to demonstrable mortality at the population level. Influenza-related pediatric deaths became reportable to the US Centers for Disease Control and Prevention in 2004. From 2004 to 2016, between 37 (in the 2011–2012 influenza season) and 288 (in the 2009–2010 influenza season) annual deaths due to LCI were reported in children younger than 18 years in the United States. These deaths are undoubtedly an underestimate given that health care workers do not routinely test for influenza, that the tests are imperfectly sensitive, and that influenza virus may initiate the sequence of events leading to death but may no longer be detectable at the time of testing. Studies in the United States have shown that among children who died of influenza, the illness progressed rapidly to death, often within 72 hours of clinical onset, further emphasizing the importance of prevention. Although children with underlying medical conditions are at increased risk for death from influenza, a substantial proportion of influenza-attributable pediatric mortality occurs in otherwise healthy children, many of whom die before they are admitted to the hospital.

Although global surveillance for influenza is extensive, limited data are available that specifically address influenza burden in children in low-resource settings. Outside of research studies conducted in these areas, few clinical diagnoses of influenza are confirmed in the laboratory. Nevertheless, the available data show an important and disproportionately high burden of influenza among young children in low-resource settings compared with children of a similar age in more developed areas. As in temperate settings, influenza attack rates vary from year to year in tropical settings. Recent studies in young children in Bangladesh and Senegal during the 2013 season reported laboratory-confirmed clinical influenza attack rates of 24.5% and 18.0%, respectively, for all circulating strains of influenza. Although these rates are high, comparable attack rates in young children in the United States in other nonpandemic years have been reported. Even if attack rates of influenza are similar in young children in low- and high-resource settings, morbidity and mortality of influenza are likely to be higher in low-resource settings, given population characteristics (eg, malnutrition), reduced or delayed access to health care, and less extensive use of pneumococcal and Hib vaccines.

A worldwide meta-analysis of data collected between 1995 and 2010 reported that the number of new episodes of influenza-associated severe acute lower respiratory infections (ALRIs) in children younger than 5 years was 15-fold greater in developing countries than in developed countries. That same meta-analysis estimated between 28,000 and 111,500 deaths occurred in children younger than 5 years from influenza-related ALRIs in 2008. It was estimated that up to 99% of these deaths occurred in low-income countries. A study in Bangladesh between 2008 and 2010 found that children younger than 5 years are hospitalized for influenza-associated illness at substantially higher rates than adults. The study estimated that 113,000 of 19,331,302 (0.6%) children younger than 5 years are hospitalized annually for influenza, compared with 16,000 of 132,920,875 (0.01%) persons at least 5 years of age. The study also reported that rates of hospitalization for influenza among young children in Bangladesh are disproportionately high when compared with influenza hospitalization rates among children of the same age in the United States.

Influenza infection in children has consequences beyond the direct medical outcomes outlined earlier. Children shed influenza virus longer and in larger amounts than adults and, thus, play a major role in the transmission of influenza in families and society. Influenza places a high medical and societal burden on children, their families, and communities. This burden is evident in school absenteeism, parents’ missed days from work, and wages lost as a result. In one study in Finland, school and day-care absenteeism is highest among children younger than 3 years, and parental days missed from work are higher as well. A US-based study showed a similar trend, with parents of influenza-infected children missing an average of 1 day of work for every 3 days of school missed by a child attributable to influenza. These numbers are likely an underestimate of the burden of influenza, as they reflect only those children who sought medical care for their illness and do not account for illnesses that occurred on non-school days.

Vaccines

Vaccination is the leading approach for the prevention of influenza, and many influenza vaccines are available on the global market. These vaccines fall into 2 broad categories: parenterally administered nonreplicating vaccines and intranasally (IN) administered live-attenuated vaccines. Current vaccines are all designed with the same goal of inducing immunity to the hemagglutinin (HA) and/or neuraminidase (NA) surface glycoproteins of the influenza virus. As the HA and NA of the virus undergo frequent antigenic drift, the seasonal influenza vaccine is reformulated as often as twice annually to match the strains projected to circulate in the following influenza season. The WHO recommends influenza strains that should be included in the seasonal influenza vaccines (for both the Northern and Southern hemispheres’ vaccine compositions) based on global epidemiologic and virologic surveillance, which has been undertaken by the Global Influenza Surveillance and Response System (GISRS) for more than 50 years. The GISRS tracks the evolution of influenza viruses as well as the emergence of influenza strains with the potential to cause pandemics.

Currently marketed influenza vaccines for nonpandemic use are trivalent or quadrivalent. Trivalent vaccines contain 3 total strains: 2 influenza A strains (one H1N1 and one H3N2) as well as 1 influenza B lineage strain; quadrivalent influenza vaccines contain an additional B lineage influenza strain. It has proven difficult to predict which B lineage will circulate in a given year, and in some years both B lineages circulate concurrently. Thus, quadrivalent influenza vaccines were developed to include both influenza B lineages (Victoria and Yamagata) that currently circulate in humans. Quadrivalent vaccines were first licensed in the United States for use in the 2013 to 2014 influenza season.

There are 2 categories of seasonal influenza vaccine currently available on the global market. Intramuscularly (IM) or intradermally (ID) injected, nonreplicating influenza virus vaccines, which can be further classified based on production substrate (egg based or cell culture based); types of preparation (whole virus, split-virion, subunit, or fully recombinant vaccines); dose (0.25-mL pediatric, 0.5-mL adult), and by presence or absence of adjuvant (MF59). The other category of approved influenza vaccine is the live-attenuated influenza vaccine (LAIV), which is administered IN. Because of the time required for influenza vaccine manufacturing, testing, packaging, and distribution, seasonal vaccines are generally available only by late summer or early fall.

This section focuses on seasonal influenza vaccines (as opposed to pandemic vaccines), licensed primarily in the United States for children, defined here as individuals younger than 18 years. Influenza vaccines are not currently licensed anywhere in the world for infants younger than 6 months. For children 6 to 23 months old, the only available vaccines are inactivated influenza vaccines (IIVs). Nonadjuvanted inactivated vaccines are the only approved option for children younger than 2 years, except in Canada where an MF59-adjuvanted trivalent IIV was approved for children 6 to 23 months of age in 2015. For children older than 2 years, an LAIV is also approved in many countries. For a summary of seasonal influenza vaccines licensed for children in the United States see Table 1 .

Inactivated influenza vaccines

Safety

Clinical trials and postlicensure surveillance have shown IIVs to be highly safe. The most common adverse events associated with IIVs in all age groups are injection site reactions. In children, injection site reactions as well as fever are the most common safety concerns of IIVs and tend to be mild and short-lived. In 2010, a trivalent IIV produced by an Australian pharmaceuticals company was strongly correlated with increased rates of febrile seizures in children in Australia. Subsequent enhanced surveillance for febrile seizures in the United States and elsewhere showed a slight increase in the rates of febrile seizures among children who had received IIVs. The febrile seizure risk among children in the United States was noted to be elevated in some years and not others and more so when IIV was coadministered with 13-valent pneumococcal conjugate vaccines or diphtheria, tetanus, and pertussis vaccines. In all cases the risk for febrile seizures in the United States was determined to be substantially lower than observed in 2010 in Australia.

Although for most children IIVs are very safe, they may pose a safety risk to individuals with severe egg allergies. Residual egg protein may remain in most influenza vaccines as the virus for the vaccine is grown in embryonated hens’ eggs. Eggs are not used in the production of cell culture-based vaccines; however, these vaccines may still contain trace amounts of egg proteins. There is currently one cell culture-based vaccine on the market for children at least 4 years of age. The recombinant trivalent vaccine is the only entirely egg-free vaccine, but it is not licensed for use in individuals younger than 18 years. Nonetheless, individuals with egg allergy should receive influenza vaccines (including egg-based vaccines) unless they have had a severe reaction to a prior influenza immunization. For individuals with severe egg allergy, egg-based vaccines should be administered by a physician trained to recognize and manage allergic responses. For more detailed instructions, see Fig. 1 .

Recommendations regarding influenza vaccination of persons who report allergy to eggs: Advisory Committee on Immunization Practices, United States, 2016 to 17 Influenza season.

( Data from CDC. Flu vaccine and people with egg allergies. Available at: https://www.cdc.gov/flu/protect/vaccine/egg-allergies.htm . Accessed April 17, 2017.)

Immunogenicity

Nonreplicating vaccines elicit an immune response primarily against the HA component of the influenza virus. HA is one of the glycoproteins on the surface of the influenza virus and functions in the attachment of the virus to the host cells. Neutralizing antibodies specific to HA are the predominant means by which IIVs confer immunity against influenza, although antibodies to the NA and other antibodies also play a role that is not as well understood.

The immunogenicity of IIVs in children varies by influenza strain, the formulation of the vaccine, and the underlying condition and prior exposure of the recipient to similar viruses or vaccines. Depending on the degree to which the vaccine strains match the circulating strains, seasonal influenza vaccines will confer more or less protection, as antibody against influenza is for the most part strain specific. Therefore, antibody against one type or subtype of influenza may provide modest to no protection against other types or subtypes of influenza.

Older children tend to have a strong antibody response, and just one dose of IIV is enough to confer protective immunity. Children younger than 9 years may have reduced antibody responses and should receive 2 doses of IIV at least 4 weeks apart the first time they are vaccinated against influenza. Once children have been primed with 2 doses of IIV, they are recommended to receive a single dose of vaccine in subsequent years. A young child may also be primed with 2 single doses of influenza vaccine across 2 influenza seasons. For more information on vaccine priming and appropriate dosing for children, refer to Fig. 2 .

Influenza vaccine dosing algorithm for children aged 6 months through 8 years: Advisory Committee on Immunization Practices, United States, 2016 to 17 influenza season.

( Data from Grohskopf LA, Sokolow LZ, Broder KR, et al. Prevention and control of seasonal influenza with vaccines. MMWR Recomm Rep 2016;65(5):1–54.)

Efficacy and Effectiveness

IIVs have demonstrated efficacy and effectiveness across broad age groups and among different populations over many influenza seasons. Vaccine efficacy generally refers to the performance of a vaccine in protecting against a previously defined clinical or laboratory outcome during clinical trials. Vaccine effectiveness describes a vaccine’s performance against the same outcomes in nonrandomized settings, as observed after licensure. Estimates of vaccine efficacy and effectiveness may vary between studies depending on the vaccine match, population (age and comorbid conditions), and study outcome. It is, therefore, difficult to systematically compare point estimates of vaccine efficacy across trials, unless the studies define the outcome in the same way and administer the same vaccine in the same study season. Efficacy and effectiveness tend to be greater when the vaccine virus strains more closely match the circulating virus strains.

A meta-analysis of randomized controlled trials of influenza vaccine efficacy over 12 influenza seasons showed IIV had a pooled efficacy of 59% (95% confidence interval [CI], 51%–67%) among those aged 18 to 65 years. Although no trials in children 2 to 17 years of age met inclusion criteria for this particular meta-analysis at the time of publication, many clinical trials have been conducted on the efficacy of seasonal influenza vaccine in children ( Table 2 ). Among children aged 1 to 16 years in a multiyear study in Nashville, Tennessee, efficacy against culture-confirmed clinical influenza was 91.4% and 77.3%, respectively, during H1N1 and H3N2 years. There were too few laboratory-confirmed episodes to evaluate by narrower age strata. In a randomized controlled trial in healthy children aged 6 to 23 months, vaccine efficacy was 66% (95% CI, 34%–82%) against culture-confirmed clinical illness in the first year but could not be assessed in the second year because of low influenza attack rates. A clinical trial in Europe in 2007 to 2008 and 2008 to 2009 randomized healthy influenza vaccine-naïve children aged 6 months to less than 72 months to receive IIV, MF59 adjuvanted IIV, or a noninfluenza control vaccine. Vaccine efficacy was 43% and 86%, respectively, for IIV and adjuvanted IIV versus the noninfluenza control vaccine against all LCI illness across both influenza seasons. In a multinational study among children 3 to 8 years of age, vaccine efficacy of a quadrivalent IIV was 55.9% against polymerase chain reaction–confirmed clinical illness of any severity.

Table 2

Individually randomized controlled trials of influenza vaccines in children, 1985 to 2013 influenza seasons

Study Years	Study Location	Age Group	Influenza Vaccine	Vaccine Strains	Number of Doses of Vaccine	Control Vaccine	Clinical Outcome Measure	Laboratory Outcome Measure	N	Circulating Strain	Vaccine Efficacy (95% CI)	Attack Rate of Control Group (%)
Trials with non-influenza vaccine control group
1985–1990	United States (Nashville, Tennessee)	1–16 y	Study y 1 : bivalent inactivated vaccine a Study y 2–5 : trivalent inactivated vaccine a All y : bivalent cold adapted a	Study y 1 : A/Dunedin/6/83, A/Chile/1/83, A/Korea/1/82, A/Philippines/2/82 Study y 2 : A/Texas/1/85, A/Chile/1/83, A/Bethesda/1/85, A/Mississippi/1/85 Study y 3 : A/Kawasaki/9/86, A/Taiwan/1/86, A/Bethesda/1/85, A/Leningrad/360/86 Study y 4 : A/Kawasaki/9/86, A/Taiwan/1/86, A/Los Angeles/2/87, A/Sichuan/2/87 Study y 5 : A/Kawasaki/9/86, A/Taiwan/1/86, A/Los Angeles/2/87, A/Shanghai/11/87	1 dose of vaccine either IN or injected IM	Double control intranasal: placebo IM injection: placebo (y 1), monovalent influenza B vaccine (y 2–5)	Influenza-like illness or other upper respiratory illness	Culture	791	H1N1 y	Cold-adapted : 95.5 (66.7–99.4)	7.1
											IIV : 91.4 (63.8–98.0)
										H3N2 y	Cold-adapted : 67.7 (1.1–89.5)	4.3
											IIV : 77.3 (20.3–93.5)
1996–1997	United States	15–71 mo	LAIV (Aviron, Mountain View, California)	A/Texas/36/91-like (H1N1), A/Wuhan/359/95-like (H3N2), B/Harbin/7/94-like	1 or 2 IN doses; 2 doses given 60 d apart	Placebo	Symptomatic fever, runny nose or nasal congestion, sore throat, cough, headache, muscle aches, chills, vomiting, otitis media	Culture	LAIV : 189 Control : 99	One-dose regimen
										All strains	89 (65–96)	14.1
										H3N2	87 (47–97)	8.1
										B	91 (46–99)	6.1
									LAIV : 849 Control : 410	2-dose regimen
										All strains	94 (88–97)	18.0
										H3N2	96 (90–99)	12.0
										B	91 (78–96)	7.6
1996–1998	United States	26–85 mo	LAIV (Aviron, Mountain View, California)	A/Shenzhen/227/95-like (H1N1), A/Wuhan/359/95 (H3N2), B/Harbin/7/94-like	1 IN dose	Placebo	Lower respiratory tract disease and/or otitis media with or without fever	Culture	Study y 1 LAIV : 1070 Control : 532	Study y 1
										All strains	93 (87–96)	17.7
										H3N2	95 (88–97)	11.8
										B	91 (79–96)	6.9
									Study y 2 LAIV : 917 Control : 441	Study y 2
										All strains	87 (78–93)	12.7
										H3N2 (matched)	100 (54–100)	0.9
										H3N2 (unmatched)	86 (75–92)	11.6
										B	100 (79–100)	0.2
1999–2001	United States (Pittsburgh)	6–24 mo	IIV (Fluzone, Aventis Pasteur, Swiftwater, Pennsylvania)	Study y 1 : A/Beijing/262/95 (H1N1), A/Sydney/15/97 (H3N2), B/Yamanashi/166/98 Study y 2 : A/New Caledonia/20/99 (H1N1), A/Panama/2007/99 (H3N2), B/Yamanashi/166/98	2 IM injections, 4 wk apart	Placebo	Upper respiratory tract infection accompanied by fever (≥38°C) and/or AOM	Culture	Study y 1 IIV : 273 Control : 138 Study y 2 IIV : 252 Control : 123	Against influenza
										All strains	Study y 1 : 66 (34–82)	15.9
											Study y 2 : −7 (−247–67)	3.3
										Against AOM
										All strains	Study y 1 : −0.28	35.8
											Study y 2 : −19.5	59.5
2000–2002	Belgium, Finland, Israel, Spain, United Kingdom	6 to <36 mo	LAIV (Wyeth Vaccines Research, Marietta, Pennsylvania)	Study y 1 : A/New Caledonia/20/99 (H1N1), A/Sydney/05/97 (H3N2), B/Yamanashi/166/98 Study y 2 : A/New Caledonia/20/99 (H1N1), A/Panama/2007/99 (H3N2), B/Victoria/504/2000	Study y 1 : 2 IN doses, 35 ±7 d apart Study y 2 : 1 IN dose	Placebo	Influenza-like illness, pneumonia, AOM	Study y 1 : serology Study y 2 : PCR	Study y 1 LAIV : 951 Control : 665 Study y 2 LAIV : 640 Control : 450	Study y 1
										All strains	85.9 (76.3–92.0)	13.4
										All vaccine-matched strains	85.4 (74.3–92.2)	10.8
										H1N1	91.8 (80.8–97.1)	7.7
										H3N2	ND	0.2
										B	72.6 (38.6–88.9)	3.5
										Study y 2
										All strains	85.8 (78.6–90.9)	30.9
										All vaccine-matched strains	88.7 (82.0–93.2)	29.1
										H1N1	90.0 (56.3–98.9)	3.1
										H3N2	90.3 (82.9–94.9)	22.4
										B	81.7 (53.7–93.9)	5.1
2000–2003	China, Hong Kong, India, Malaysia, the Philippines, Singapore, Taiwan, Thailand	12 to <36 mo	LAIV (Wyeth Vaccines Research, Marietta, Pennsylvania)	Study y 1 : A/New Caledonia/20/99 (H1N1), A/Sydney/05/97 (H3N2), B/Yamanashi/166/98 Study y 2 : A/New Caledonia/20/99 (H1N1), A/Panama/2007/99 (H3N2), B/Yamanashi/166/98	Study y 1 : 2 IN doses, 28 d apart Study y 2 : 1 dose in study y 2	Placebo	Influenza-like illness as described in Belshe et al, 1998	Culture	Study y 1 LAIV : 1653 Control : 1111 Study y 2 Primed LAIV : 881 Unprimed LAIV : 503 Primed control : 759 Unprimed control : 494	Study y 1
										All strains	70.1 (60.9–77.3)	16.4
										All vaccine-matched strains	72.9 (62.8–80.5)	12.5
										H1N1	80.9 (69.4–88.5)	7.3
										H3N2 (unmatched)	90.0 (71.4–97.5)	2.4
										B (matched)	44.3 (6.2–67.2)	3.2
										Study y 2
										All strains	64.2 (44.2–77.3)	11.9
										All vaccine-matched strains	84.3 (70.1–92.4)	9.9
										H1N1	—	N/R
										H3N2	86.3 (71.4–94.1)	N/R
										B (unmatched)	—	N/R
2001–2002	South Africa, Brazil, Argentina	6 to <36 mo	LAIV (Wyeth Vaccines, Marietta, Pennsylvania)	Study y 1 : A/New Caledonia/20/99-like (H1N1), A/Panama/2007/99-like (H3N2), B/Yamanashi/166/98-like, B/Victoria/504/00-like Study y 2 : A/New Caledonia/20/99-like (H1N1), A/Panama/2007/99-like (H3N2), B/Victoria/504/00-like	Study y 1 : 1 or 2 intranasal doses Study y 2 : 1 dose	Placebo	Lower respiratory tract disease and/or otitis media with or without fever	Culture	Study y 1 LL: 944 PP: 474 Study y 2 LL/L: 339 PP/P: 342	Study y 1 b
										LL vs PP
										All strains	72.0 (61.9–79.8)	N/R
										All vaccine-matched strains	73.5 (63.6–81.0)	N/R
										H1N1	NC	N/R
										H3N2	72.7 (60.7–81.5)	N/R
										B (matched)	81.4 (64.2–91.2)	N/R
										Study y 2
										LL/L vs PP/P
										All strains	46.6 (14.9–67.2)	N/R
										All vaccine-matched strains	73.6 (33.3–91.2)	N/R
										H1N1	94.0 (62.0–99.9)	N/R
										H3N2	49.4 (−253.0–95.4)	N/R
										B (matched)	−102.4 (−2137.1–71.0)	N/R
2007–2008	Germany and Finland	6 to <72 mo	Study y 1 : ATIV (Fluad, Novartis Vaccines), subunit TIV (Aggripal S1, Novartis Vaccines) Study y 2 : ATIV and split TIV (Influsplit SSW, GlaxoSmithKline Biologicals)	Study y 1 : A/Solomon Islands/3/2006 (H1N1), A/Wisconsin/67/2005 (H3N2), B/Malaysia/2506/2004 Study y 2 : A/Brisbane/59/2007 (H1N1), A/Brisbane/10/2007 (H3N2), B/Florida/4/2006	2 doses, 28 d apart	Meningococcal C conjugate vaccine (Menjugate); 6 to <12 mo; tick-borne encephalitis vaccine (Encepur children); 12 to <72 mo	Influenza-like illness	rRT-PCR	ATIV : 1937 TIV : 1772 Control : 993	All strains ATIV	86 (74–93) c	4.7
										All strains TIV	43 (15–61)	4.7
										Vaccine-matched strains ATIV	89 (78–95)	4.1
										Vaccine-matched strains TIV	45 (16–64)	4.1
2009	South Africa	6–60 mo; HIV-infected	TIV (VAXIGRIP, Sanofi-Aventis, Lyon, France)	A/Brisbane/59/2007(H1N1), A/Uruguay/716/2007(H3N2), B/Florida/4/2006	2 IM doses, 1 mo apart	Placebo	Influenza-like illness	Culture and RT-PCR	TIV : 203 Control : 200	All strains	24.7 (−64.7–66.4)	8.5
2010–2011	Multinational study, 15 sites in Bangladesh, Dominican Republic, Honduras, Lebanon, Panama, the Philippines, Thailand, and Turkey	3–8 y	QIV (GlaxoSmithKline Vaccines)	A/California/7/2009 (H1N1), A/Victoria/210/2009 (H3N2), B/Brisbane/60/2008 (Victoria lineage), B/Florida/4/2006 (Yamagata lineage)	1 or 2 IM injections depending on priming	Hepatitis A vaccine (Havrix, GSK Vaccines)	Influenza-like illness	rRT-PCR	QIV : 2379 Control : 2398	Any severity
										All strains	55.9 (39.1–67.3)	4.67
										All vaccine-matched strains	45.1 (9.3–66.8)	2.34
										H1N1	55.6 (21.3–74.9)	1.58
										H3N2	57.6 (28.5–74.9)	1.96
										B/Yamagata (matched)	100 (— to 100)	0.08
										B/Victoria (matched)	47.2 (12.4–68.2)	1.79
										Moderate-severe
										All strains	73.1 (47.1–86.3)	2.17
										H1N1	76.5 (30.3–92.1)	0.71
										H3N2	82.4 (49.1–93.9)	0.96
										B/Yamagata (matched)	100.0 (— to 100.0)	0.04
										B/Victoria (matched)	42.1 (47.1–77.2)	0.5
2013	Bangladesh	24–59 mo	LAIV (Nasovac-S, SIIL, Pune, India; lot 167E2002)	A/California/7/2009 (H1N1)-like, A/Victoria/361/2001 (H3N2)-like, B/Wisconsin/1/2010 (Yamagata lineage)-like	1 IN dose	Placebo	Symptomatic fever (≥38.0°C), upper respiratory illness, AOM, meningitis, or sepsis	rRT-PCR	LAIV : 1174 Control : 587	All strains	41.0 (28.0–51.6)	24.5
										All vaccine-matched strains	57.6 (43.6–68.0)	15.8
										H1N1	50.0 (9.2–72.5)	3.6
										H3N2	60.4 (44.8–71.6)	12.3
										B (matched)	0.0 (−1001–90.9)	0.2
										B (unmatched)	6.5 (−43.0–38.8)	5.3
2013	Senegal	2 to <5 y	LAIV (Nasovac- STM, SIIL, Pune, India; lot 167E2002)	A/California/7/2009 (H1N1)-like, A/Victoria/361/2001 (H3N2)-like, B/Wisconsin/1/2010 (Yamagata lineage)-like	1 IN dose	Placebo	Fever (>37.5°C), cough, sore throat	rRT-PCR	LAIV : 1174 Control : 587	All strains	0.0 (−26.4–20.9)	18.0
										All vaccine- matched strains	−6.1 (−50.0–25.0)	8.0
										H1N1	−9.7 (−62.6–26.1)	6.2
										H3N2	—	0.0
										B (matched)	9.5 (−88.9–56.6)	1.7
										B (unmatched)	7.3 (−26.3, 31.9)	10.6
Comparative trials of influenza vaccines; no noninfluenza vaccine control group
2002	145 sites in Belgium, Finland, Germany, Greece, Israel, Italy, the Netherlands, Norway, Poland, Portugal, Spain, Switzerland, the United Kingdom	6–17 y	LAIV (Wyeth Vaccines Research, Marietta, Pennsylvania) TIV split virion (Aventis Pasteur, Lyon, France)	LAIV : A/New Caledonia/20/99 (H1N1), A/Panama/2007/99 (H3N2), B/Hong Kong/330/01 TIV : Caledonia/20/99—IVR-116, A/Panama/2007/99—RESVIR-17, B/Shanghai/7/97	1 dose IN or IM injection	None	Influenza-like illness, pneumonia, AOM	rRT-PCR	LAIV : 1111 TIV : 1109	All strains	31.9 (1.1–53.5) d	6.6 e
										All vaccine-matched strains	34.7 (3.9–56.0)	6.4
										H1N1	100 (−8.4–100.0)	0.5
										H3N2	0.6 (−141.8–59.2)	1.1
										B	36.3 (0.1–59.8)	4.8
2002	Belgium, Czech Republic, Finland, Germany, Italy, Poland, Spain, Switzerland, the United Kingdom	6–71 mo	LAIV (Wyeth Pharmaceuticals, Marietta, Pennsylvania) TIV split virion (Aventis Pasteur, Lyon, France)	LAIV : A/New Caledonia/20/99 (H1N1), A/Panama/2007/99 (H3N2), B/Hong Kong/330/01 TIV : A/Panama/2007/99 (H3N2), A/New Caledonia/20/99 (H1N1), B/Shangdong/7/97	LAIV : 2 IN doses, 35 ±7 d apart TIV : 1 IM injection	None	At least 1: fever (≥38.0°C rectal or 37.5°C axillary), shortness of breath, pulmonary congestion, pneumonia, AOM, or wheezing 2 or more: rhinorrhea, pharyngitis, cough, muscle aches, chills, headache, irritability, decreased activity, or vomiting	Serology and PCR	LAIV : 1050 TIV : 1035	All strains	52.4 (24.6–70.5) d	5.8 e
										All vaccine-matched strains	52.7 (21.6–72.2)	4.8
										H1N1	100.0 (42.3–100.0)	0.8
										H3N2	−97.1 (−540.2–31.5)	0.6
										B	68.0 (37.3–84.8)	3.6
2004	249 sites in the United States, 12 countries in Europe and the Middle East, and 3 countries in Asia	6–59 mo	LAIV (FluMist, MedImmune) TIV (United States and Asia: Fluogen, Aventis Pasteur; Europe and Middle East: Fluzone, Aventis Pasteur)	A/New Caledonia/20/99 (H1N1), A/Wyoming/3/2003 (H3N2)-like, B/Jilin/20/2003	1 or 2 IN (LAIV) or IM injection (TIV) doses (28–42 d apart if 2 doses)	Placebo	Protocol-defined influenza symptoms	Culture	LAIV : 4179 TIV : 4173	All strains	54.9 (45.4–62.9) d	8.6 e
										All vaccine-matched strains	44.5 (22.4–60.6)	2.4
										H1N1 (matched)	89.2 (67.7–97.4)	0.7
										H3N2 (matched)	—	0
										H3N2 (unmatched)	79.2 (70.6–85.7)	4.5
										B	27.3 (−4.8–49.9)	1.7

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