The influenza virus is the etiologic agent of the flu, causing annual epidemics
which are associated with excessive hospitalizations and mortality, particularly
among the elderly and those suffering from underlying conditions, such as cardiopulmonary
and metabolic diseases and immunodeficiencies.
Prevention of infection by the influenza virus by means of vaccination is recommended
for all of these populations and their contacts and also anyone who does not wish
to catch the flu.
the Advisory Committee on Immunization Practices (ACIP), in the USA,
and the American Academy of Pediatrics
recommended routine influenza vaccination for children aged 6 to 23 months, considering
this age group to be at high risk of increased severity of infection by the influenza
virus. This recommendation was based on epidemiological surveys that demonstrated
that children in this age group exhibit hospitalization rates that are greater
than or equal to those observed in other high risk groups.
Furthermore, use of the inactivated influenza vaccine with children at this age
has been proven to be safe and to have acceptable efficacy, backing up the recommendation.
The Department of Infectious Diseases of the Brazilian Society of Pediatrics also
recommended the inclusion of influenza vaccination for children from 6 to 23 months
in the vaccination schedule they presented at the XIV Brazilian Congress of Pediatric
Infectology, held at Foz do Iguaçu (state of Paraná, Brazil) in
April 2005. In the light of this recommendation, in conjunction with other significant
epidemiological data on the role of children in the transmission, morbidity and
mortality of influenza epidemics, it is considered appropriate to discuss the
The objective of this review is to use medical literature and Brazilian
epidemiological data to briefly characterize the impact of the flu and the benefits,
immunogenicity, safety and efficacy of vaccinating healthy children against the
influenza virus, especially in the 6 to 23 months age group.
were run on MEDLINE, LILACS and the Cochrane Library and specialists were consulted
on the following themes: influenza, influenza vaccine, infants, vaccine efficacy
and adverse events. The most relevant articles were selected from those that reported
on randomized, double-blind and controlled clinical trials, in addition to national
or international epidemiological population-based incidence studies.
and epidemiology of the influenza virus
The influenza virus is an
orthomyxovirus with an envelope and single-strand segmented RNA. It has two surface
glycoproteins, which play important roles in its antigenicity and pathogenicity,
named hemagglutinin (HA) and neuraminidase (NA).
Influenza viruses are classified into one of three subtypes, A, B or C, with the
first of these being associated with the greatest antigenic variation in HA and
Three HA (H1, H2 and H3) and two NA (N1 and N2) variants are associated with infections
in human beings,
although other variants, such as H5N1, that are typically observed in other species,
have caused infections in humans who have had contact with poultry.
viruses cause annual epidemics that are associated with significant morbidity
and mortality and have a major impact on public health, with around 20 thousand
deaths/year and 140 thousand hospitalizations/year, on average, in the USA.
The populations at greatest risk present more severe infections by the influenza
virus and excessive levels of pneumonia, mortality and hospital admissions, particularly
among the elderly, cardiopulmonary patients and people with immunodeficiencies.
temperate countries and in the South and Southeast of Brazil, influenza virus
epidemics typically occur during the winter months.
In regions with tropical climates, however, they can happen at any time of year,
sometimes more than once a year, and may be associated with rainy seasons.
The circulation of the influenza virus is global and annual epidemics and pandemics
are associated with population immunity to the subtype in circulation, with the
epidemics being associated with small variations within a subtype (antigenic drift)
and pandemics with major antigenic variation (antigenic shift).
Impact of the influenza virus on children
Glezen et al.
described the typical progression of an influenza epidemic, with an average duration
of 6 to 8 weeks, starting among schoolchildren and later passing to economically
active adults. The role of children in the spread of these viruses is clear, having
also been reported in more recent epidemiological studies.
do not only disseminate the influenza virus, but can also present significant
morbidity associated with flu infections, with less typical and sometimes more
severe clinical manifestations.
Encephalitis cases caused by the influenza virus have been described in children.
In the USA, 121 deaths were associated with influenza infections in patients less
than 18 years old, with just 26% of these having risk factors for greater severity.
fact that hospital admissions among children under 5 years of age increase in
frequency during influenza epidemics has been known for several years.
Nevertheless, since the respiratory syncytial virus (RSV) is one of the principal
agents of hospitalization in children less than 1 year old with lower respiratory
tract infections, and since RSV exhibits similar seasonality to the influenza
virus, the real importance of the influenza virus was initially undervalued in
this age group.
Later, Neuzil et al.
and Izurieta et al.
demonstrated that the influenza virus was also associated with hospitalizations
and morbidity to as significant an extent as RSV. These authors were able to characterize
the varying periods of predominance of each agent and the rates of hospitalization
associated with each one. Since then other studies have confirmed these authors'
findings, demonstrating the true impact of influenza virus infections in children,
associated with increased severity, increase in the number of medical consultations,
use of antibiotics, parents' absenteeism from work and the appearance of secondary
respiratory infections are the most important cause of mortality in children under
5 years in developing countries.
Despite bacterial etiology being considered more associated with mortality, viruses
present very significant frequency and are associated with secondary infections.
Kim et al.
demonstrated an association between influenza epidemics and an increased number
of identifications of pneumococcus in invasive infections, which was confirmed
experimentally by Peltola et al.
and by O'Brien et al.
in case control studies of pneumococcal pneumonia. The experimental efficacy of
vaccination and of treating influenza with antivirals for preventing mortality
in mice by invasive pneumococcal infection were also recently confirmed.
The impact of the influenza virus on children in
Currently, the epidemiology of the influenza virus is well known
in Brazil and its seasonality has been well characterized, with outbreaks taking
place in the winter months in the South and Southeast regions.
Brazil has referral centers for the diagnosis and identification of influenza
viruses and is an active participant in the World Health Organization (WHO) influenza
surveillance network, contributing with data to support the decision on the annual
composition of the influenza vaccine to be used in the Southern Hemisphere.
The morbidity of influenza virus infections in Brazilian children has not been
analyzed systematically; however, there are several different published studies
in which the influenza virus appears as a cause of acute respiratory infections
and hospital admissions.
the Ribeirão Preto area (São Paulo state), an increase was observed
in the number of hospitalizations due to pneumonia and bronchiolitis in children
under 5 years of age during the months that correspond to the greatest incidence
of RSV and the influenza virus.
During an influenza outbreak in 2004, the virus was detected in 13% of children
under 1 year old admitted to hospital for bronchiolitis or pneumonia,
in addition to concomitant occurrence with severe pneumococcal pneumonia.
Paiva et al.
studied an influenza outbreak in Iporanga (São Paulo state) and observed
that 84.3% of cases were in children and adolescents up to 19 years of age. Moura
detected the influenza virus in 22.3% of children under 5 years old seen at emergency
and/or health centers in Salvador (Bahia state). In the same city, a longitudinal
follow-up study of children seen at day care who had presented respiratory symptoms
detected the influenza virus in 7% of cases.
In Rio de Janeiro (Rio de Janeiro state), Sutmoller et al.
and Nascimento et al.
detected the influenza virus in 10 and 6.7% of children under 5 years old with
acute respiratory infections (ARI), respectively. In Porto Alegre (Rio Grande
do Sul state), Stralioto et al.
detected the virus in 1.7% of children from 0 to 5 years old with ARI seen at
an emergency room. In a longitudinal study of children with respiratory symptoms
in the city of Fortaleza (Ceará state) Arruda et al.
detected the influenza virus in 5.7% of patients with upper airway infections.
without the mass of epidemiological data available on North-America, we can infer
that the influenza virus is an important causal agent of ARI in Brazilian children
under 5 years old and that it is associated with increased hospital admissions
for lower airway infections, with significant morbidity.
The different types of influenza vaccines are listed in
Table 1 with their main characteristics, indications and course of doses. The
vaccine presentations available in Brazil are listed in Table 2.
Table 2 -
Influenza vaccines available in Brazil
Inactivated vaccines are the
primary means of preventing influenza infection, due to the vast experience of
their use worldwide.
Vaccines made with whole viruses exhibit good levels of immunogenicity, but have
greater reactogenicity too, in particular causing fever in children and, therefore,
are not indicated for this age group.
Split vaccines, whether from fragmented or subunit viruses, offer a good safety
profile, with the first being more immunogenic than the second and both being
indicated for children under 12 years.
vaccines are inactivated vaccines in which the HA and NA influenza virus surface
antigens are incorporated into virosome (virus-like) particles that have an adjuvant
This type of vaccine offers similar immunogenicity and safety to other vaccines.
A nasal formulation was used in a clinical trial with children and later abandoned
due to a link with facial paralysis.
a trivalent, live, attenuated, cold-adapted influenza vaccine (LAIV) was licensed
in the USA.
An attenuated vaccine had been previously used in the now-extinct USSR and had
been studied in the USA since the 1960s, being now revisited with nasal administration.
The vaccine that is currently licensed in the USA must be stored frozen at -15
ºC and was approved for use with healthy children and adults from 5 to 49
years of age.
The attenuated influenza vaccine was shown to be safe, immunogenic and effective,
although there are doubts about its safety in small children, the elderly and
patients with immunosuppression, despite having been tested in clinical trials
with these populations.
This vaccine can induce systemic humoral and mucosal immunoresponse, in addition
to cellular immunoresponse, being capable of inducing cross-protection against
other influenza strains.
A liquid formulation that does not require freezing is currently in phase III
vaccines are modified annually, based on WHO recommendations.
Since 1947, the WHO has coordinated epidemiological flu surveillance centers in
many parts of the world, which today total 110 laboratories in 80 countries which
systematically collect samples of respiratory secretions from patients with flu-like
disease. The influenza viruses isolated are then sent to global influenza surveillance
centers, which are responsible for the complete identification of the viruses,
with detailed antigenic descriptions. At the end of February every year, a group
of WHO specialists meet to consider the epidemiological data collected during
the previous year and to recommend which influenza strains will be most likely
to cause epidemics the following year and should therefore be part of the vaccine
to be used that winter in the Northern Hemisphere. The same procedure takes place
at the end of September in Melbourne, Australia to define the composition of the
Southern Hemisphere vaccine.
New approaches for producing influenza vaccines
are being studied.
Some examples are the production of vaccines with cell cultures, vaccines using
influenza genetic material, methods to increase the potency of current vaccines
with the use of new adjuvants and new forms of administering the inactivated vaccines.
Vaccines derived from cell cultures would not depend on fertilized eggs, which
could lead to increased influenza vaccine production capacity.
Safety of the influenza vaccines in children
safety of trivalent inactivated and attenuated influenza vaccines has been tested
in clinical trials and reviews of databases on vaccine-related adverse events.
reviewed adverse reactions at a clinical research center in the USA over a 5-year
period (1985-90) in 277 children aged 1 to 16 years who were given 635 doses of
vaccine. No severe reactions were observed and local reactions occurred in 6 to
14% of those who were vaccinated. In another randomized, double-blind, placebo
controlled multicenter study of 2,032 patients with asthma, 712 of whom were aged
3 to 18 years, no asthma exacerbations were observed among those vaccinated up
to 2 weeks after vaccination.
syndrome has not been linked with the inactivated vaccine in children, but the
relatively small number of patients in the studies compromise their power for
detecting extremely rare events.
revised all articles published on the inactivated influenza vaccine up to 2004,
and described reactogenicity varying significantly between whole and split virus
vaccines, with the latter being less reactogenic. The majority of reactions were
local or febrile and varied significantly between studies.
Smith et al.,
in a review published by the Cochrane Library, confirmed that local reactions
and fever were the most common adverse events after influenza vaccination, whether
with inactivated or attenuated vaccine. The authors emphasized the scant experience
from clinical trials with inactivated vaccines in children less than 2 years old,
although clinical experience is relevant.
Recently, McMahon et al.
performed a 14-year review, 12 years (1990 to 2002) before and 2 years (2002-2003)
after the recommendation for vaccinating children under 24 months, using data
from the Centers for Disease Control and Prevention (CDC) Vaccine Adverse Event
Report System (VAERS). The authors searched for reports of adverse reactions after
vaccination with the inactivated influenza vaccine in children under 2 years old.
They found reports of 166 events, 62 (37%) of which were related to influenza
vaccine alone and 104 (63%) ocurred after influenza vaccine was given together
with other vaccines. Fever (59%) was the most common event, followed by rash (42%),
convulsions (28%) and local reactions (28%). It is estimated that in 2002/2003,
around 424,667 to 513,403 children were vaccinated, with 61 reports of adverse
events, with a frequency of 0.014 to 0.012%. Just 18 of these were associated
with influenza vaccination alone, significantly reducing this rate to around 3:100,000
doses. These data are corroborated by information obtained from the São
Paulo state health department, which also showed that reports of adverse events
after influenza vaccination in children was not very representative (Sato HK,
personal communication at a meeting of the Department of Infectious Diseases of
Sociedade de Pediatria de São Paulo, held in São Paulo, SP, on August
Izurieta et al.
used the CDC VAERS system to review reports of adverse events in children and
adults receiving the attenuated influenza vaccine during the period after its
licensure, from 2003 to 2005. A total of 2.5 million people were vaccinated, with
460 adverse events reported, including seven reports of anaphylactic shock, two
of Guillian-Barré syndrome, one of facial paralysis and eight asthma exacerbations.
In 16% of the adverse event reports the vaccine had been given to patients for
whom it was not indicated, i.e. healthy individuals aged 5 to 49 years. These
data corroborate previous observations made in clinical trials that characterized
the attenuated influenza vaccine as safe.
In a clinical trial conducted by Piedra et al.,
the attenuated vaccine demonstrated a satisfactory safety profile, including in
the children under 5 years of age.
The immunogenicity of the inactivated influenza vaccine is directly proportional
In children under 6 years of age, approximately 40 to 80% exhibit seroconversion
after a single dose of vaccine, while for children over 6 years the rate of seroconversion
rises to 70 to 100%.
More than 50% of children under 3 years old and around 30% of children up to 9
years old are seronegative for the influenza virus.
This fact results in the recommendation to give two doses of vaccine to the 6
months to 9 years age group the first year of vaccination, with just one dose
being required annually thereafter.
Recently, Englund et al.
studied the immunogenicity of the inactivated influenza vaccine in children from
6 to 23 months. These authors assessed the immunogenicity of the classic course
of two doses with a 1 month interval and compared it with a course using a 6 month
interval between doses, using vaccines with the same antigenic composition. Overall,
rates of seroconversion were from 58 to 88%, varying for each of the three antigens,
and no differences were observed between the two vaccine courses. These results
support the idea that the reduced response to the influenza vaccine in children
is associated with the need for previous contact with the antigen and thus could
favor the immunization of small children with doses left over from previous years
with the second dose being given during the annual vaccination season.
attenuated influenza vaccine exhibits seroconversion rates of 61 to 96% measured
by hemagglutination inhibition titers that are elevated four times or more.
In another study the rates of seroconversion were 90, 50 and 16%, varying according
to influenza subtype.
In truth, there is no exclusive measure of seroconversion, since the vaccine also
induces mucosal and cellular immunity.
Efficacy of the influenza vaccine in children
The results of clinical trials investigating the efficacy of the inactivated
influenza vaccine vary greatly, depending on the primary objective of each study.
In general, efficacy against confirmed influenza virus infection varies from 31
to 91% and is not uniform for the subtypes. Protective efficacy for acute otitis
media (AMO) is more variable, being reported as absent by some authors and up
to 36% by others.
Hurwitz et al.
studied the inactivated influenza vaccine in 150 children from 2 to 5 years old
who attended daycare. Protective efficacy against influenza infections, confirmed
by serology, was 45% for influenza virus B and 31% influenza virus A. Prevention
of acute febrile flu-like disease was studied by Colombo et al.
in 344 healthy children aged 1 to 6 years, in a randomized, controlled trial.
The vaccinated group (n = 177) exhibited a 67% reduction in episodes of acute
febrile disease when compared with the control group (n = 167) (12.4 vs. 37.7%,
In a review of clinical trials conducted from 1985 to 1990,
Neuzil et al.
studied the efficacy of the inactivated influenza vaccine in healthy children
less than 16 years old. With the primary outcome of protection against influenza
infections confirmed by culture, efficacy was 77 to 91% against the A/H3N2 and
A/H1N1 influenza viruses, respectively.
Hoberman et al.
studied the protective efficacy against AMO of the inactivated influenza vaccine
in children from 6 to 24 months who attended daycare during two flu seasons. The
authors did not observe differences between the vaccinated group and a placebo
group, but up to 66% protection from influenza infections was observed, confirmed
by culture. Heikkinen et al.
assessed children from 1 to 3 years of age with n = 187 in each group, vaccinated
and unvaccinated respectively, and observed a reduction of 36% in AMO episodes
(34 vs. 53%, vaccinated vs. unvaccinated). The same study reported protective
efficacy against confirmed influenza A infection of 83% (3 vs. 29%, vaccinated
and unvaccinated, respectively). Clements et al.,
in a retrospective study of 186 children from 6 to 30 months de age, reported
reductions of 32% in AMO episodes.
Kramarz et al.
reported efficacy in asthma patients for reducing asthma exacerbations after vaccination
with the inactivated influenza vaccine. Sugaya et al.
reported 67 and 44% protection against influenza A and B, respectively, in asthmatic
A study of attenuated influenza vaccine carried out by Belshe
found efficacy of 87 to 93% against confirmed infection by the influenza A virus
the first year of vaccination and 86 to 87% the second year, when the strain of
influenza A virus in circulation was different from that present in the vaccine.
The reduction in AMO was 27%. Gaglani et al.
observed reductions of 18 to 20% in the number of medical consultations for episodes
of acute respiratory infections in children vaccinated with the attenuated influenza
Jefferson et al.
reviewed the efficacy of the attenuated vaccine in healthy children, reporting
it at 79%. These authors report that the efficacy of the inactivated vaccine is
65%. The effectiveness of vaccination was 38% for the attenuated vaccine and 28%
for the inactivated vaccine, in both cases for children older than 2 years. Efficacy
for children younger than 2 years was not studied systematically, with the exception
of the investigations into AMO episodes mentioned above.
of the impact of influenza vaccination with the inactivated vaccine in schoolchildren
showed control of influenza epidemics with reductions in the total number of cases
and in viral dissemination.
The same result was recently reported for the attenuated vaccine by Piedra et.
who observed reductions in the number of medical consultations in unvaccinated
people when vaccination coverage reached 25% of schoolchildren. In Japan, the
national program for influenza vaccination of schoolchildren was associated with
reduced mortality by influenza among the elderly.
Universal influenza vaccination is currently under debate as a more effective
alternative for preventing the disease.
Acute respiratory infections
are a worldwide public health problem, with significant impact on morbidity and
mortality in children under 5 years of age and in other high-risk populations.
Vaccination is an effective measure for controlling these diseases, as has been
observed for measles and invasive Haemophilus influenzae type B infections.
Vaccination against influenza has surfaced as a new weapon in the fight to prevent
ARI in children. With the epidemiological data that are currently available on
the impact of this agent on the pediatric age group, we can infer that the benefits
of vaccination would be reductions in morbidity, observed through the reductions
in number of hospital admissions, medical consultations and antibiotic prescriptions
for healthy children during influenza epidemics.
doubt, a major impact would be felt from an influenza immunization program that
covered all schoolchildren, however, the vaccination of small groups, particularly
through programs in partnership with businesses or health insurance plans, would
be a good start for assessing the impact of influenza vaccination.
Secondary benefits, such as reductions in parents' absenteeism from work, reduced
circulation of influenza viruses at daycare centers, and even reductions in secondary
cases among family members would be another impact of vaccination against influenza
in children, which would make vaccination more cost-effective.
the current recommendation on influenza vaccination for children is that pediatricians
should indicate the vaccination of all children over 6 months old with risk factors
and for all children aged 6 to 23 months. For all other age groups, it is suggested
that the vaccine be offered, emphasizing the benefits of vaccination for the prevention
of influenza infections and their complications.