Correspondence

Intranasal Influenzavirus Vaccine in Children

N Engl J Med 1998; 339:922-923September 24, 1998

Article

To the Editor:

The encouraging results of the study conducted by Belshe et al. (May 14 issue)1 of a live attenuated influenzavirus vaccine that can be administered intranasally to young children should be placed in context. In an earlier study, we randomly assigned 5210 normal, healthy subjects to receive either attenuated or inactivated influenzavirus vaccine or placebo.2 The study subjects, who were 1 to 65 years of age, received a total of 12,500 doses of vaccine over a five-year period. In contrast to the observation by Belshe et al. that the serologic response was poorer to the A/Texas/36/91-like (H1N1) component of the live attenuated vaccine than to the A/Wuhan/359/95-like (H3N2) component,1 the rate of serologic response in our subjects was significantly greater to the A(H1N1) strain than to the A(H3N2) strain in the attenuated vaccine.2 The efficacy of the attenuated vaccine also varied widely according to year, serotype, and case definition and was lower than that reported by Belshe et al.

For the more immunogenic A(H1N1) strain, the efficacy ranged from 67 percent to 90 percent, depending on the definition of the disease, whereas for the A(H3N2) strain, the efficacy varied from 40 percent to 59 percent. The differences between these results and those of Belshe et al. may be due to a variety of factors. Nevertheless, the findings of their study may not be generalizable to all people at low risk for influenza or to all strains of influenzavirus in all years. Additional studies of this promising vaccine are warranted.

Kathryn M. Edwards, M.D.
William D. Dupont, Ph.D.
Vanderbilt University Medical Center, Nashville, TN 37232-2637

2 References

1. 1

   Belshe RB, Mendelman PM, Treanor J, et al. The efficacy of live attenuated, cold-adapted, trivalent, intranasal influenzavirus vaccine in children. N Engl J Med 1998;338:1405-1412
   Full Text | Web of Science | Medline

2. 2

   Edwards KM, Dupont WD, Westrich MK, Plummer WD Jr, Palmer PS, Wright PF. A randomized controlled trial of cold-adapted and inactivated vaccines for the prevention of influenza A disease. J Infect Dis 1994;169:68-76
   CrossRef | Web of Science | Medline

To the Editor:

In their report on the intranasal influenza vaccine, Belshe et al. state that the phenotypes of positive viral cultures were evaluated to determine whether they were wild-type virus or one of the strains in the vaccine. However, the results of the phenotyping are not reported. It would be interesting to know how long vaccine virus can be detected in nasal specimens after the vaccine has been administered.

Juan Dumois, M.D.
All Children's Hospital, St. Petersburg, FL 33701-4899

Author/Editor Response

The authors reply:

To the Editor: The study by Edwards et al. was crucial to the design of our study and is the largest study of the live attenuated intranasal influenza vaccine to date. The safety and efficacy data from that study were instrumental in the development of our trial of the vaccine's efficacy in children. Their results support the equal efficacy of the live attenuated intranasal vaccine and the inactivated injected vaccine against influenzavirus types A(H1N1) and A(H3N2) in persons with a broad range of ages (1 to 65 years).

Important differences between that study and ours in the methods of case finding, the populations studied, the vaccine components (bivalent vs. trivalent vaccine), the route of administration of the vaccine (nose drops vs. nasal spray), and the antigenic match with epidemic strains probably account for the differences in efficacy between the two studies. Our study is continuing. Children were vaccinated again last fall with a single dose of vaccine containing strains that matched the inactivated influenzavirus-vaccine strains for 1997–1998 or with placebo.

As we discussed, a serum antibody response does not appear to be the best surrogate marker of efficacy. Boyce et al. recently reported that secretory antibody developed in subjects studied at one of the sites in our efficacy field trial; secretory IgA to all three strains in the vaccine developed in approximately 80 percent of the subjects given two doses.1

Extensive studies of shedding of the strains of live attenuated influenzavirus given as monovalent vaccines2-4 or as trivalent preparations5 have been conducted. In general, one or more of the vaccine strains are shed in low quantities for up to 10 days in the respiratory secretions of vaccinated young children who are initially seronegative. In our study, the phenotype was determined for each of the 18 influenzaviruses that were recovered within 28 days of vaccination. All were vaccine virus, and all were isolated after the first dose. These strains were isolated on days 2 through 11. No virus from the vaccine was isolated after day 11 in our study.

The prevention of influenza, the reduction in febrile otitis media, and the reduction in the concomitant use of antibiotics made possible through the use of this easily administered nasal-spray vaccine represents an important advance in prophylactic medicine for children. General use of this vaccine would substantially benefit children and adults by preventing influenza and its complications.

Robert B. Belshe, M.D.
Saint Louis University, St. Louis, MO 63110-0250

William C. Gruber, M.D.
Vanderbilt University, Nashville, TN 37232-2581

Paul M. Mendelman, M.D.
Aviron, Mountain View, CA 94043

5 References

1. 1

   Boyce TG, Gruber WC, Coleman-Dockeny SD, et al. Mucosal immune response to trivalent live attenuated intranasal influenza vaccine in children. Abstracts of the Pediatric Academic Societies' Annual Meeting, New Orleans, May 1–5, 1998. The Woodlands, Texas: APS/SPR/APA, 1998:141A.
   

2. 2

   Belshe RB, Van Voris LP. Cold-recombinant influenza A/California/10/78 virus vaccine (CR-37) in seronegative children: infectivity and efficacy against investigational challenge. J Infect Dis 1984;149:735-740
   CrossRef | Web of Science | Medline

3. 3

   Anderson EL, Belshe RB, Burk B, Bartram J, Maassab HF. Evaluation of cold-recombinant influenza A/Korea (CR-59) virus vaccine in infants. J Clin Microbiol 1989;27:909-914
   Web of Science | Medline

4. 4

   Anderson EL, Newman FK, Maassab HF, Belshe RB. Evaluation of a cold-adapted influenza B/Texas/84 reassortant virus (CRB-87) vaccine in young children. J Clin Microbiol 1992;30:2230-2234
   Web of Science | Medline

5. 5

   Swierkosz EM, Newman FK, Anderson EL, Nugent SL, Mills GB, Belshe RB. Multidose, live attenuated, cold-recombinant, trivalent influenza vaccine in infants and young children. J Infect Dis 1994;169:1121-1124
   CrossRef | Web of Science | Medline

Citing Articles (2)

Citing Articles

1. 1

   Mario de Bernardi di Valserra, Alessandro Zanasi, Salvatore Ragusa, Reinhard Glück, Christian Herzog. (2002) An open-label comparison of the immunogenicity and tolerability of intranasal and intramuscular formulations of virosomal influenza vaccine in healthy adults. Clinical Therapeutics 24:1, 100-111
   CrossRef

2. 2

   Jim E. Eyles, E. Diane Williamson, H. Oya Alpar. (2000) Intranasal Administration of Influenza Vaccines. BioDrugs 13:1, 35-59
   CrossRef