New Influenza Vaccine for Children to be Administered Intranasally
August 1, 1998
Special Feature
New Influenza Vaccine for Children to be Administered Intranasally
By Hal B. Jenson, MD, FAAP
Influenza a and b virus infections have a sig- nificant effect on healthy children as well as children with underlying high-risk conditions. Attack rates in healthy children have been estimated at 10-40% per year, with lower respiratory tract complications (e.g., pneumonia, bronchiolitis) ranging from 2-25%. Excessive rates of hospitalization have been reported for children with influenza who have diseases such as severe asthma, cystic fibrosis, chronic renal disease, diabetes, sickle cell disease, or immunosuppression. Influenza vaccines are currently prepared annually from inactivated whole virus particles of the strains that are expected to be prevalent in the following influenza season. Split-virus vaccines (that may be labeled as "split," "subvirion," or "purified-surface antigen" vaccines) are prepared with an additional step that disrupts the lipid-containing membrane. The immunogenicity and side effects of split- and whole-virus vaccines are similar in adults. Only the split-virus vaccines should be used in children younger than 13 years of age, because of their decreased potential for causing febrile reactions.1
A major impediment for influenza immunization, especially of children, is the need for annual intramuscular injections. A recently developed live, attenuated influenza virus vaccine that is administered intranasally addresses this issue. The efficacy of this new vaccine was evaluated in a multicenter, double-blind, placebo-controlled trial in children 15-71 months of age.2 The vaccine included three strains antigenically equivalent to the those in the licensed, inactivated influenza virus vaccine used at the same time during the 1996-1997 influenza season: A(H1N1), A(H3N2), and B. A total of 782 children received a two-dose regimen; 288 received a single dose, and 532 received a placebo. Rhinorrhea or nasal congestion during days 2-9 after vaccination, and fever and decreased activity at two days after vaccination were significantly associated with the first dose of the vaccine, but there were no symptoms associated with the second dose. Two doses were required to induce serum antibodies to influenza A in the majority of children. Overall, after two doses of vaccine, 61% of children had antibodies to the A(H1N1) strain and 96% had antibodies to the other vaccine strains.
Vaccination significantly reduced the incidence of culture-confirmed influenza in recipients. There were 14 cases of culture-confirmed influenza among the 1070 children (1%) who received vaccine compared to 101 cases in 95 children, including six children with two distinct culture-confirmed episodes of influenza among the 532 children (18%) who received placebo. Both the one- dose regimen (89% efficacy) and two-dose regimen (94% efficacy) were efficacious against both of the influenza A and B strains circulating in 1996-1997. Vaccinated children had fewer febrile illnesses, including 30% fewer episodes of febrile otitis media (P = < 0.001), and a 29% reduction in febrile illness associated with any antibiotic use (P = < 0.001).
Topical administration of live attenuated influenza virus vaccine would have many advantages. The ease of administration as a nasal spray overcomes a significant obstacle, namely the necessity of annual intramuscular administration of the vaccine. Other obstacles to the increased use of the current influenza virus vaccine in children include the need for two doses of the initial immunization in children younger than 9 years of age, the potential for causing febrile reactions in children younger than 12 years of age, concern about side effects, and the costs of the vaccine and administration. Only 30% of high-risk persons younger than 65 years of age, and only 58% of the persons 65 years of age and older, receive appropriate vaccination against influenza. There are few data concerning the level of use of influenza vaccine in children.
Influenza is a significant cause of morbidity even in healthy children. In this study, 18% of the placebo recipients had culture-proven influenza, 20% of whom also had acute otitis media. Intranasal attenuated virus vaccine was not only efficacious in reducing the incidence of influenza, but also in reducing associated otitis media and the use of antibiotics. Considering the continuing development of antimicrobial resistance, the growing dilemmas of treating otitis media, and the $3-4 billion annual costs of treating ear infections, vaccination of young children against influenza (as well as vaccination against respiratory syncytial virus [RSV]) may be as important to decrease the need for widespread antibiotic use in children as much as for the prevention of the viral illness.
The current licensed influenza virus vaccine is recommended for children and adults at high risk for severe influenza or its complications, including children with asthma and all persons 65 years of age and older. A recent addition to the list of recommended recipients is women who will be in the second or third trimester (14 weeks' gestation) of pregnancy during the influenza season (December-March), because influenza infection may cause increased morbidity in pregnant women during this period. Pregnant women who have medical conditions that increase their risk for complications from influenza should be vaccinated before the influenza season, regardless of the stage of pregnancy. No adverse fetal effects have been associated with influenza vaccination. Of special note to pediatricians, breast-feeding is not a contraindication for influenza vaccination for either the mother or child.
In this study, the intranasal influenza vaccine was equally efficacious among all age groups. Older children were more likely to have pre-existing serum antibody, but this did not interfere with vaccine efficacy. This suggests that intranasal, topical vaccination may induce secretory IgA antibody or stimulate cellular immunity that may provide protection from infection. There was no protection afforded to household contacts against influenza.
Vaccination with influenza vaccine of persons in high-risk groups is cost-effective. However, it is uncertain if routine immunization of healthy children would be cost-effective, unless vaccination rates were high enough to affect transmission of the virus in the community. Unlike many successful vaccination programs, such a strategy for influenza would require consistent annual immunization among older children and young adults-groups that are not accustomed to receiving annual medical evaluations.
It is likely that this live attenuated vaccine, with the trade name FluMist, will be approved by the FDA and licensed in time for use for the 1999-2000 influenza season, with indications similar to the current influenza vaccine. It is possible that the vaccine may also be indicated for children prone to recurrent otitis media and to children in day care or other settings with increased exposure to influenzae. An effective intranasal vaccine would be a significant advance to improve influenza vaccination rates of children at high risk (and hopefully for physicians, nurses, and other healthcare workers, for whom annual influenza vaccination is also recommended.)
References
1. Centers for Disease Control and Prevention. MMWR Morb Mortal Wkly Rep 1998;47(RR-6):1-26.
2. Belshe RB, et al. N Engl J Med 1998;338:1405-1412.
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