Published online February 25, 2008
PEDIATRICS Vol. 121 No. 3 March 2008, pp. e568-e573 (doi:10.1542/peds.2007-1405)
This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow P3Rs: Submit a response
Right arrow Alert me when this article is cited
Right arrow Alert me when P3Rs are posted
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow E-mail this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Add to My File Cabinet
Right arrow Download to citation manager
Right arrow reprints & permissions
Citing Articles
Right arrow Citing Articles via CrossRef
Google Scholar
Right arrow Articles by Vesikari, T.
Right arrow Articles by Forrest, B. D.
PubMed
Right arrow PubMed Citation
Right arrow Articles by Vesikari, T.
Right arrow Articles by Forrest, B. D.
Related Collections
Right arrow Infectious Disease & Immunity

ARTICLE

Safety and Tolerability of Cold-Adapted Influenza Vaccine, Trivalent, in Infants Younger Than 6 Months of Age

Timo Vesikari, MDa, Aino Karvonen, MDa, Helen M. Smith, BScb, Andrew Dunning, PhDc, Ahmad Razmpour, PhDc, Melanie K. Saville, MB, BSb, William C. Gruber, MDc and Bruce D. Forrest, MDc

a Vaccine Research Center, University of Tampere Medical School, Tampere, Finland
b Wyeth Vaccines Research, Taplow, United Kingdom
c Wyeth Vaccines Research, Pearl River, New York


   ABSTRACT
TOP
 ABSTRACT
METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
OBJECTIVE. Young children are at high risk for influenza-related complications. Vaccination of close household contacts is recommended to provide indirect protection to children <6 months of age. Studies have shown that live, cold-adapted influenza vaccine, trivalent, is efficacious in children. To assess the risks associated with inadvertent exposure of infants to vaccine viruses from vaccinated contacts, this study was designed to evaluate the safety and tolerability of cold-adapted influenza vaccine, trivalent, administered intranasally to healthy children 6 to <24 weeks of age.

METHODS. Healthy infants aged 6 to <16 weeks and 16 to <24 weeks, respectively, were randomly assigned to receive 2 doses of influenza vaccine, or placebo intranasally 35 ± 7 days apart. Reactogenicity events were monitored for 11 days after each dose. Other adverse events were monitored through 28 to 35 days after dose 2.

RESULTS. Of the infants aged 6 to <16 weeks, 31 received influenza vaccine and 28 received placebo, and of those aged 16 to <24 weeks, 30 received influenza vaccine and 31 received placebo. In the 6- to <16-week cohort, more influenza vaccine, recipients experienced irritability (66.7% vs 35.7%) and runny nose or nasal congestion (63.3% vs 33.3%) after dose 1 but not dose 2. There were no significant increases in any other reactogenicity events or adverse events in the vaccine recipients compared with the placebo group.

CONCLUSIONS. Although there was an increase in mild reactogenicity events in children 6 to <16 weeks of age, cold-adapted influenza vaccine, trivalent, was generally well tolerated in infants 6 to <24 weeks of age. These findings support further evaluation of cold-adapted influenza vaccine, trivalent, in infants <6 months of age.

Key Words: live attenuated influenza vaccine • immunogenicity • infants • clinical trial

Abbreviations: TIV—trivalent inactivated influenza vaccine • LAIV—live attenuated influenza vaccine • CAIV-T—cold-adapted influenza vaccine, trivalent • RE—reactogenicity event • AE—adverse event • SAE—serious adverse event

Influenza infection is associated with a significant excess of outpatient visits and hospitalizations in young children.1–5 The majority of children hospitalized for influenza or influenza-related complications are previously healthy children.6 The Advisory Committee on Immunization Practices and the American Academy of Pediatrics currently recommend influenza immunization for all children between 6 and 59 months of age,7,8 and vaccination of close household contacts is recommended to provide indirect protection to children <6 months of age.7

Live attenuated influenza vaccine (LAIV) (FluMist, cold-adapted influenza vaccine, trivalent [CAIV-T]; MedImmune, Gaithersburg, MD) is currently approved in the United States for use in healthy children and adolescents aged 2 to 17 years and adults aged 18 to 49 years and is not licensed outside the United States. Recently published data from clinical trials suggest that LAIV has a higher relative efficacy compared with TIV in children <5 years of age.9–11 Additional data are needed for children <12 months of age however, in light of an unexplained observation in 1 study of higher hospitalization rates in this population.11

Because LAIV replicates in the nose of a vaccinated individual, the potential for transmission of vaccine viruses from vaccinated contacts to unvaccinated infants has been raised as a concern. Children infected with wild-type influenza virus can shed virus in nasal secretions for ≤14 days after onset of symptoms.12–15 Similarly, vaccine virus can be detected in nasal secretions from children after immunization with CAIV-T.16 In a recent study of children aged between 9 and 36 months attending day care, 80% of vaccinated children shed vaccine virus for a mean of 8 days postvaccination, whereas transmission of shed vaccine virus to an unvaccinated contact was documented in only 1 instance, and the estimated transmission rate was low (0.58%).16 Because of the theoretical possibility that vaccine virus could be transmitted by household contacts to unvaccinated infants, this study was designed to evaluate the safety and tolerability of CAIV-T in healthy young infants 6 to <24 weeks of age.


   METHODS
TOP
 ABSTRACT
 METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Participants
Eligible subjects were infants 6 to <24 weeks of age who were ≥37 weeks’ gestational age with a birth weight ≥2500 g and in good health as assessed by medical history, physical examination, and clinical judgment. Exclusion criteria included serious chronic disease including progressive neurologic disease; Down syndrome or other known cytogenetic disorders; known or suspected disease of the immune system, receipt of immunosuppressive therapy, or the presence of an immunosuppressed or immunocompromised individual in the same household; receipt of blood products from birth through the conclusion of the study; documented history of hypersensitivity to egg or egg protein or any other component of study vaccine or placebo; receipt of any live virus vaccine within 1 month before enrollment or intent to receive another live vaccine within 1 month of vaccination in the study; intent to administer any other investigational vaccine or agent from 1 month before enrollment through the conclusion of the study; receipt of any influenza treatment within 2 weeks before enrollment, including prophylactic use of antiviral medication, or any influenza vaccine at any time before entry into the study; any respiratory illness with wheezing within 2 weeks of each dose of study vaccine; receipt of aspirin or aspirin-containing products in the 2 weeks before vaccination or anticipated use during the study; and any medical condition that, in the opinion of the investigator, might interfere with interpretation of the study results. Concomitant routine childhood vaccination with inactivated vaccines was permitted during this study.

Study Design
This randomized, double-blind, placebo-controlled study was conducted between May and December 2002 at the University of Tampere Vaccine Research Center, which has clinics in Tampere, Turku, Espoo, Pori, Lahti, and Jyväskylä, Finland. The study was conducted in accordance with the Declaration of Helsinki and in compliance with the ethical principles of the International Conference on Harmonization Guideline for Good Clinical Practice. The study was approved by the independent ethics committee of Tampere University Hospital District. For each subject, parents provided written, informed consent.

Subjects were prospectively randomly assigned in a 1:1 ratio to receive 2 doses of CAIV-T or placebo 35 (± 7) days apart. Subjects were stratified by age at first vaccination into 2 age groups: 6 to <16 weeks and 16 to <24 weeks. Both vaccine doses were administered after the 2001 influenza season and before the start of the 2002 season.

Vaccine and Placebo
CAIV-T (manufactured by Wyeth Vaccines Research, Marietta, PA) contained 3 cold-adapted reassortant influenza virus strains representing the 3 strains recommended by the World Health Organization for the 2001–2002 influenza season (A/New Caledonia/20/99 [H1N1], A/Panama/2007/99 [H3N2], and B/Victoria/504/2000)17 grown in specific pathogen-free chicken eggs. Each 0.2-mL dose contained ~107 ± 0.5 fluorescent focus units of each of the vaccine strains. The vaccine was shipped to the study sites at 2 to 8°C, where it was stored at that temperature until just before administration. CAIV-T was administered intranasally with a spray applicator (~0.1 mL into each nostril). Placebo consisted of 0.2 mL of the physiologic saline administered intranasally with a spray applicator (~0.1 mL into each nostril).

Study Evaluations
The primary study end point was the tolerability of CAIV-T based on reactogenicity events (REs) reported within 11 days of the first or second dose of study vaccine. REs were predefined events that included fever (≥38°C rectal temperature), runny nose, nasal congestion, cough, vomiting, activity level, appetite, and irritability. The subjects’ parents or guardians were instructed to assess the presence or absence of each event and to record the assessment on diary cards.

Secondary study end points included the occurrence of adverse events (AEs), unscheduled physician visits, and use of prescription and nonprescription medications. An AE was defined as any clinically significant event, including those that required any prescription or nonprescription medication, required an unscheduled physician visit, resulted in withdrawal from the study, or resulted in any other medically significant event. AEs were monitored through days 28 to 35 after the second dose of vaccine. REs that also met the definition of an AE were recorded as both. A serious AE (SAE) was any event that resulted in death, was life-threatening, required or prolonged hospitalization, resulted in a persistent or significant disability, or resulted in cancer.

Statistical Analyses
The study was designed to have ≥80% power to detect absolute differences in event probabilities between the CAIV-T and placebo groups, ranging from .188 to .267, depending on the probability of the event occurring in the placebo group (.05–.40). Within each age cohort, the study was designed to have 80% power to detect absolute differences in event probabilities ranging from .305 to .380. The occurrence of systemic reactions was compared between groups by a 2-sided Fisher's exact test. P values were not adjusted for multiple comparisons. The dose 1 and 2 safety analysis populations consisted of all of the subjects who received the first or second dose of study vaccine, respectively, as actually administered.


   RESULTS
TOP
 ABSTRACT
 METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
Subject Characteristics
The study population was composed of 120 subjects who were randomly assigned to receive CAIV-T (n = 61) or placebo (n = 59). There were 59 infants in the 6- to <16-week cohort (31 CAIV-T and 28 placebo) and 61 in the 16- to <24-week cohort (30 CAIV-T and 31 placebo). Treatment groups were well matched with regard to age at first vaccination, gender, and ethnicity (Table 1). A total of 114 subjects (95%) completed the study (Fig 1). Of the 6 subjects withdrawn from the study, 1 subject in the CAIV-T group withdrew because of parental request, and 1 CAIV-T recipient was withdrawn after experiencing a convulsion without fever possibly related to study vaccine 2 days after vaccination. The next day the child was fully recovered and was discharged from the hospital. Four placebo recipients were withdrawn because they did not receive the second dose within the 28- to 42-day window for vaccination. The mean age ± SD at first vaccination was 12.0 ± 2.2 weeks for the 6- to <16-week cohort and 20.0 ± 2.5 weeks for the 16- to <24-week cohort. The mean interval between vaccine doses was the same for CAIV-T and placebo recipients (30.9 ± 3.7 days). Concomitant routine childhood vaccination with inactivated vaccines was permitted during this study, and the numbers of patients receiving the diphtheria-tetanus-pertussis, Haemophilus b conjugate, and inactivated polio vaccines were similar among CAIV-T and placebo recipients (data not shown).


View this table:
[in this window]
[in a new window]

  		TABLE 1 Demographic Characteristics

 

Figure 1
View larger version (26K):
[in this window]
[in a new window]

  		FIGURE 1 Patient flow through the trial.

 
Safety Analysis
More CAIV-T than placebo recipients experienced any RE during the 11 days after dose 1 (80.3% vs 72.7%; P = .383). Conversely, after dose 2, REs were reported less frequently in CAIV-T than in placebo recipients (69.5% vs 72.2%; P = .837). In the 6- to <16-week cohort, runny nose or nasal congestion and irritability occurred significantly more frequently in CAIV-T than in placebo recipients (63.3% vs 33.3%, P = .034; and 67.7% vs 35.7%, P = .035, respectively), and there was a trend toward decreased appetite in the CAIV-T group (23.3% vs 3.7%; P = .054) after the first dose but not after the second dose (Table 2). There were no statistically significant differences in any REs between treatment groups after dose 2 in the 6- to <16-week cohort. Similarly, in the 16- to <24-week cohort, runny nose or nasal congestion and irritability were the most frequently reported REs among CAIV-T and placebo recipients, but the incidence was similar in both treatment groups (Table 2). In the 16- to <24-week cohort, cough was significantly more common in placebo than CAIV-T recipients after dose 2 (39.3% vs 10.7%; P = .029).


View this table:
[in this window]
[in a new window]

  		TABLE 2 Reactogenicity Events After Dose 1 or 2

 
The most frequently reported AEs in both age cohorts and after each dose were bodily discomfort, fever, and rhinitis (Table 3). There was no significant difference in the incidence of any AE between treatment groups in either age cohort, although there was a trend for bodily discomfort to be more common among CAIV-T recipients in the 6- to <16-week cohort after dose 1 (P = .055).


View this table:
[in this window]
[in a new window]

  		TABLE 3 Adverse Events Reported in >5% of Subjects After Dose 1 or 2

 
A single SAE was reported in the 6- to <16-week cohort: a case of pyelonephritis with fever 18 days after the second dose of CAIV-T that was considered by the investigator to be unrelated to study vaccine. Three SAEs were reported in the 16- to <24-week cohort: (1) the subject described above who experienced a convulsion (manifesting as lethargy) 2 days after receiving the first dose of CAIV-T that was considered possibly related to vaccine and led to withdrawal of the subject from the study; (2) severe vomiting 16 days after receiving the second dose of CAIV-T that was considered by the investigator to be unrelated to study treatment; and (3) an upper respiratory tract infection with fever and otitis media beginning 3 days after receiving the first dose of placebo. All of these subjects recovered fully.


   DISCUSSION
TOP
 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
This study assessed the safety and tolerability of intranasal CAIV-T (a refrigerated formulation of LAIV) compared with placebo in infants 6 to <24 weeks of age at the time of vaccination. Young children are at high risk for influenza-related complications, and vaccination of household contacts is recommended to provide indirect protection to children <6 months of age for whom vaccination is not currently recommended.7 Despite the very low risk of transmission of live influenza vaccine viruses to nonvaccinated individuals, it is possible that children in this age group may be exposed to vaccine viruses through close contact with vaccinated playmates, caregivers, and other household members.

The findings from this study suggest that transmission of CAIV-T vaccine virus to a young infant is not likely to pose a significant health risk. Doses of CAIV-T containing 107 infectious viruses of each vaccine strain were well tolerated in infants 16 to <24 weeks of age. The incidence and profile of REs were similar to those reported in larger studies in older children 6 to 71 months of age in which the safety of CAIV-T viruses has been clearly established.10,16,18–20 In contrast, this study suggests that some REs may be increased in infants 6 to <16 weeks of age who receive CAIV-T.

Despite a possible increase in reactogenicity, additional safety, efficacy, and immunogenicity trials in infants <6 months of age may be warranted in view of the significant burden of influenza in this age group. To date, efficacy of CAIV-T has been demonstrated in children as young as 6 months of age.9–11 In a study of 1616 children 6 to <36 months of age attending day care, efficacy of CAIV-T in preventing culture-confirmed influenza was 85% and 89% in the first and second years of the study, respectively.10 CAIV-T has also demonstrated superior efficacy compared with TIV in children as young as 6 months of age. In a study of 2187 subjects aged 6 to 71 months, there were 53% fewer cases of influenza caused by circulating influenza viruses among CAIV-T than TIV recipients, and there were fewer medically attended visits for respiratory tract infections and fewer days of school or day care missed by CAIV-T recipients.9 These findings have been confirmed recently in a larger study of 8475 children 6 to 59 months of age in which there were 55% fewer cases of culture-confirmed influenza in CAIV-T compared with TIV recipients.11

In addition, CAIV-T has been shown to protect against circulating influenza strains that are not antigenically matched to the vaccine strains. During a period of antigenic drift in circulating influenza H3N2 viruses, the vaccine viruses in CAIV-T were ≤86% effective in protecting children and adults against antigenically drifted influenza strains.21,22 More recently, in a study in children 6 to 59 months of age, there were 58% fewer episodes of influenza caused by antigenically drifted influenza strains among CAIV-T than TIV recipients.11

Despite a relatively small sample size, this study has demonstrated that CAIV-T was well tolerated when administered to infants 6 to 24 weeks of age. The symptoms that were observed in infants 6 to <16 weeks of age were mild and transient. These findings suggest that there should not be adverse clinical consequences in the unlikely event of transmission of CAIV-T vaccine virus from a vaccinated contact to a young infant. Immunogenicity and efficacy of CAIV-T in this young population has not been evaluated to date. The results presented here support further evaluation of CAIV-T in young infants. However, such studies should be performed with caution, because recent studies have suggested that vaccination with CAIV-T may be associated with an increased risk of wheezing in children <24 months of age and with increased risk of hospitalization in children 6 to 11 months of age.11 In our study, no such adverse experiences were observed, but the number of subjects in this study was too small to detect these rare events.


   ACKNOWLEDGMENTS
 
This work was supported by MedImmune and Wyeth Vaccines Research.

We thank the participating subjects and the parents of the children; Päivi Salonen, RN, the nurse coordinator; the investigators and study nurses of the vaccine study clinics of Tampere, Turku, Espoo, Pori, Lahti, and Jyväskylä; the clinical testing laboratory staff; and the clinical research associates and scientists at Wyeth and MedImmune. We also thank Gerard P. Johnson, PhD, and Janet Stead, BM, BS, who provided medical writing and editorial assistance.


   FOOTNOTES
 
Accepted Aug 3, 2007.

Address correspondence to Timo Vesikari, MD, University of Tampere Medical School/FM3, Biokatu 10, 33520 Tampere, Finland. E-mail: timo.vesikari{at}uta.fi

Financial Disclosure: Drs Smith, Dunning, Saville, Gruber, and Forrest are current or former employees of Wyeth Vaccines Research, codevelopment partner for FluMist with Aviron (now MedImmune).

Data from this study were presented at the International Conference on Options for the Control of Influenza; October 7–11, 2003; Okinawa, Japan; and the annual meeting of the Pediatric Academic Societies; April 29 to May 2, 2006; San Francisco, CA.

This trial has been registered at www.clinicaltrials.gov (identifier NCT00192348).


   REFERENCES
TOP
 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 

  1. Neuzil KM, Mellen BG, Wright PF, Mitchel EF Jr, Griffin MR. The effect of influenza on hospitalizations, outpatient visits, and courses of antibiotics in children. N Engl J Med.2000; 342 (4):225 –231[Abstract/Free Full Text]
  2. Heikkinen T, Silvennoinen H, Peltola V, et al. Burden of influenza in children in the community. J Infect Dis.2004; 190 (8):1369 –1373[CrossRef][ISI][Medline]
  3. Loughlin J, Poulios N, Napalkov P, Wegmuller Y, Monto AS. A study of influenza and influenza-related complications among children in a large US health insurance plan database. Pharmacoeconomics.2003; 21 (4):273 –283[CrossRef][ISI][Medline]
  4. O'Brien MA, Uyeki TM, Shay DK, et al. Incidence of outpatient visits and hospitalizations related to influenza in infants and young children. Pediatrics.2004; 113 (3 pt 1):585 –593[Abstract/Free Full Text]
  5. Principi N, Esposito S, Marchisio P, Gasparini R, Crovari P. Socioeconomic impact of influenza on healthy children and their families. Pediatr Infect Dis J.2003; 22 (10 suppl):S207 –S210[ISI][Medline]
  6. Quach C, Piche-Walker L, Platt R, Moore D. Risk factors associated with severe influenza infections in childhood: implication for vaccine strategy. Pediatrics.2003; 112 (3). Available at: www.pediatrics.org/cgi/content/full/112/3/e197
  7. Advisory Committee on Immunization Practices; Smith NM, Bresee JS, et al. Prevention and control of influenza: recommendations of the Advisory Committee on Immunization Practices (ACIP) [published correction appears in MMWR Morb Mortal Wkly Rep. 2006;55(29):800]. MMWR Recomm Rep.2006; 55 (RR-10):1 –42[Medline]
  8. American Academy of Pediatrics, Committee on Infectious Diseases. Recommendations for influenza immunization of children. Pediatrics.2004; 113 (5):1441 –1447[Abstract/Free Full Text]
  9. Ashkenazi S, Vertruyen A, Arístegui J, et al. Superior relative efficacy of live attenuated influenza vaccine compared with inactivated influenza vaccine in young children with recurrent respiratory tract infections. Pediatr Inf Dis J.2006; 25 (10):870 –879[CrossRef][ISI][Medline]
  10. Vesikari T, Fleming DM, Aristegui JF, et al. Safety, efficacy, and effectiveness of cold-adapted influenza vaccine-trivalent against community-acquired, culture-confirmed influenza in young children attending day care. Pediatrics.2006; 118 (6):2298 –2312[Abstract/Free Full Text]
  11. Belshe RB, Edwards KM, Vesikari T, et al. Comparative safety and efficacy of live attenuated and inactivated influenza vaccines in infants and young children. N Engl J Med.2007; 356 (7):685 –696[Abstract/Free Full Text]
  12. Frank AL, Taber LH, Wells CR, et al. Patterns of shedding of myxoviruses and paramyxoviruses in children. J Infect Dis.1981; 144 (5):433 –441[ISI][Medline]
  13. Hall CB, Douglas RG Jr, Geiman JM, Meagher MP. Viral shedding patterns of children with influenza B infection. J Infect Dis.1979; 140 (4):610 –613[ISI][Medline]
  14. Long CE, Hall CB, Cunningham CK, et al. Influenza surveillance in community-dwelling elderly compared with children. Arch Fam Med.1997; 6 (5):459 –465[Abstract]
  15. Wright PF, Ross KB, Thompson J, Karzon DT. Influenza A infections in young children: primary natural infection and protective efficacy of live-vaccine-induced or naturally acquired immunity. N Engl J Med.1977; 296 (15):829 –834[Abstract]
  16. Vesikari T, Karvonen A, Korhonen T, et al. A randomized, double-blind study of the safety, transmissibility and phenotypic and genotypic stability of cold-adapted influenza virus vaccine. Pediatr Infect Dis J.2006; 25 (7):590 –595[CrossRef][ISI][Medline]
  17. World Health Organization (WHO). Recommended composition of influenza virus vaccines for use in the 2001–2002 season. Wkly Epidemiol Rec.2001; 76 (8):58 –61[Medline]
  18. Belshe RB, Mendelman PM, Treanor J, et al. The efficacy of live attenuated, cold-adapted, trivalent, intranasal influenza virus vaccine in children. N Engl J Med.1998; 338 (20):1405 –1412[Abstract/Free Full Text]
  19. Tam JS, Capeding MRZ, Lum LCS, et al. Efficacy and safety of a live attenuated, cold-adapted influenza vaccine, trivalent against culture-confirmed influenza in young children in Asia. Pediatr Infect Dis J.2007; 26 (7):619 –628[CrossRef][ISI][Medline]
  20. Piedra PA, Yan L, Kotloff K, et al. Safety of the trivalent, cold-adapted influenza vaccine in preschool-aged children. Pediatrics.2002; 110 (4):662–672
  21. Belshe RB, Gruber WC, Mendelman PM, et al. Efficacy of vaccination with live attenuated, cold-adapted, trivalent, intranasal influenza virus vaccine against a variant (A/Sydney) not contained in the vaccine. J Pediatr.2000; 136 (2):168 –175[CrossRef][ISI][Medline]
  22. Nichol KL, Mendelman PM, Mallon KP, et al. Effectiveness of live, attenuated intranasal influenza virus vaccine in healthy, working adults: a randomized controlled trial. JAMA.1999; 282 (2):137 –144[Abstract/Free Full Text]
PEDIATRICS (ISSN 1098-4275). ©2008 by the American Academy of Pediatrics




This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow P3Rs: Submit a response
Right arrow Alert me when this article is cited
Right arrow Alert me when P3Rs are posted
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow E-mail this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Add to My File Cabinet
Right arrow Download to citation manager
Right arrow reprints & permissions
Citing Articles
Right arrow Citing Articles via CrossRef
Google Scholar
Right arrow Articles by Vesikari, T.
Right arrow Articles by Forrest, B. D.
PubMed
Right arrow PubMed Citation
Right arrow Articles by Vesikari, T.
Right arrow Articles by Forrest, B. D.
Related Collections
Right arrow Infectious Disease & Immunity