Tingting Yi

Safety and efficacy of live attenuated influenza vaccine in children 2-7 years of age

Three pivotal trials supported the licensure of live attenuated influenza vaccine (LAIV) for children > or =2 years of age: 2 placebo-controlled studies each conducted over 2 seasons, and a 1-year trial comparing LAIV with trivalent inactivated influenza vaccine (TIV). Analyses were conducted to evaluate the safety and efficacy of LAIV in the subgroup of children > or =2 years of age from these trials. Efficacy was demonstrated compared with placebo in children aged 2-7 years in seasons with matched strains (69.2% [95% CI: 52.7, 80.4] and 94.6% [95% CI: 88.6, 97.5]), seasons with primarily mismatched strains (87% [95% CI: 77.0, 92.6]), and during late season epidemics (73.8% [95% CI: 40.4, 89.4]). Compared with TIV recipients, LAIV recipients aged 2-5 years had 52.5% (95% CI: 26.7, 68.7) and 54.4% (95% CI: 41.8, 64.5) fewer cases of influenza illness against matched and mismatched strains, respectively. No unusual or unexpected adverse reactions were noted. The adverse reactions most commonly associated with LAIV were runny nose/nasal congestion and low-grade fever. Hospitalizations and medically significant wheezing were increased in children 6-11 and 6-23 months of age who received LAIV, respectively, but were not increased in children 2-5 years of age.

Shedding of Live Vaccine Virus, Comparative Safety, and Influenza-Specific Antibody Responses after Administration of Live Attenuated and Inactivated Trivalent Influenza Vaccines to HIV-Infected Children

HIV-infected children (N=243), >or=5 to <18 years old, receiving stable antiretroviral therapy, were stratified by immunologic status and randomly assigned to receive intranasal live attenuated influenza vaccine (LAIV) or intramuscular trivalent inactivated influenza vaccine (TIV). The safety profile after LAIV or TIV closely resembled the previously reported tolerability to these vaccines in children without HIV infection. Post-vaccination hemagglutination inhibition (HAI) antibody responses and shedding of LAIV virus were also similar, regardless of immunological stratum, to antibody responses and shedding previously reported for children without HIV infection. LAIV should be further evaluated for a role in immunizing HIV-infected children.

Phase 1 study of the safety and immunogenicity of a live, attenuated respiratory syncytial virus and parainfluenza virus type 3 vaccine in seronegative children.

Background: Respiratory syncytial virus (RSV) and parainfluenza virus type 3 (PIV3) are important causes of lower respiratory tract illness and hospitalization in young children. Currently, there is no licensed vaccine against RSV or PIV3. Methods: In this randomized, phase 1, double-blind, placebo-controlled, dose-escalating study, 49 healthy RSV/PIV3-seronegative children 6 to <24 months of age were randomized 2:1 to receive 3 doses (at 104, 105, or 106 median tissue culture infective dose [TCID50]) of MEDI-534 (a live, attenuated RSV/PIV3 chimeric virus vaccine candidate) or placebo at 2-month intervals. Solicited adverse events (SEs) and unsolicited adverse events (AEs) were recorded during days 0 to 28 after each dose. Nasal wash samples were collected 3 times (days 7–10, 12–18, and 28–34) after each dose and at unscheduled illness visits. Blood for antibody response was collected at baseline and 28 days after each dose. Subjects were followed for 180 days after the last dose or to the end of the RSV season. Results: Overall, there was no difference in the incidence of SEs and AEs between the RSV/PIV3 vaccine and placebo arms. Runny/stuffy nose was the most commonly reported SE. Medically attended lower respiratory illness rates were balanced between treatment arms, and there was no evidence of enhanced RSV disease or vaccine-related serious AEs. Vaccine virus was detected in most vaccinees on days 7 to 10 after dose 1 in a dose-dependent manner. Seroresponse to RSV and PIV3 was highest in subjects receiving the 106 dosage. Conclusions: The safety profile and vaccine take as measured by shedding and/or seroresponse in this RSV/PIV3-seronegative pediatric population support the continued development of this RSV/PIV3 pediatric vaccine candidate.

Immunogenicity and safety of a quadrivalent live attenuated influenza vaccine in children.

Background: Influenza B viruses from 2 lineages cocirculate annually. Because the single B strain contained in trivalent vaccines may not match the major circulating strain, adding a second B virus could enhance protection. This study compared the safety and immunogenicity of an investigational quadrivalent Ann Arbor strain live attenuated influenza vaccine (Q/LAIV) with that of 2 trivalent vaccines (T/LAIV), each containing a B strain from a different lineage. Methods: This randomized, double-blind study was designed to demonstrate the immunologic noninferiority of Q/LAIV compared with T/LAIV in children 2–17 years of age by comparing postdose geometric mean titers of hemagglutination inhibition antibodies. Children were randomized 3:1:1 to receive Q/LAIV or 1 of 2 T/LAIV vaccines. Those subjects who were 9–17 years of age received 1 dose, and those 2–8 years of age received 2 doses 1 month apart. Serum immune responses were evaluated 1 month after dose 1 (dose 2 for influenza vaccine–naive subjects aged 2–8 years). Results: Q/LAIV was noninferior to T/LAIV: upper bounds for all four 95% confidence intervals for the postdose geometric mean titer ratios (T/LAIV divided by Q/LAIV) were ⩽1.5, the predefined noninferiority margin. The overall seroresponse rates (4-fold rise) were comparable between treatment groups. Safety events were comparable, except that fever was more common after dose 1 in Q/LAIV subjects (5.1%) than in T/LAIV subjects (3.1%) 2–8 years of age. Conclusions: The immunogenicity of Q/LAIV was noninferior to that of T/LAIV in children aged 2–17 years; safety was also comparable. Q/LAIV may broaden the protection against influenza B strains provided by current trivalent influenza vaccines.

Safety and immunogenicity following administration of a live, attenuated monovalent 2009 H1N1 influenza vaccine to children and adults in two randomized controlled trials.

Background The safety, tolerability, and immunogenicity of a monovalent intranasal 2009 A/H1N1 live attenuated influenza vaccine (LAIV) were evaluated in children and adults. Methods/Principal Findings Two randomized, double-blind, placebo-controlled studies were completed in children (2–17 y) and adults (18–49 y). Subjects were assigned 4∶1 to receive 2 doses of H1N1 LAIV or placebo 28 days apart. The primary safety endpoint was fever ≥38.3°C during days 1–8 after the first dose; the primary immunogenicity endpoint was the proportion of subjects experiencing a postdose seroresponse. Solicited symptoms and adverse events were recorded for 14 days after each dose and safety data were collected for 180 days post-final dose. In total, 326 children (H1N1 LAIV, n = 261; placebo, n = 65) and 300 adults (H1N1 LAIV, n = 240; placebo, n = 60) were enrolled. After dose 1, fever ≥38.3°C occurred in 4 (1.5%) pediatric vaccine recipients and 1 (1.5%) placebo recipient (rate difference, 0%; 95% CI: –6.4%, 3.1%). No adults experienced fever following dose 1. Seroresponse rates in children (H1N1 LAIV vs. placebo) were 11.1% vs. 6.3% after dose 1 (rate difference, 4.8%; 95% CI: –9.6%, 13.8%) and 32.0% vs. 14.5% after dose 2 (rate difference, 17.5%; 95% CI: 5.5%, 27.1%). Seroresponse rates in adults were 6.1% vs. 0% (rate difference, 6.1%; 95% CI: –5.6%, 12.6%) and 14.9% vs. 5.6% (rate difference, 9.3%; 95% CI: –0.8%, 16.3%) after dose 1 and dose 2, respectively. Solicited symptoms after dose 1 (H1N1 LAIV vs. placebo) occurred in 37.5% vs. 32.3% of children and 41.7% vs. 31.7% of adults. Solicited symptoms occurred less frequently after dose 2 in adults and children. No vaccine-related serious adverse events occurred. Conclusions/Significance In subjects aged 2 to 49 years, two doses of H1N1 LAIV have a safety and immunogenicity profile similar to other previously studied and efficacious formulations of seasonal trivalent LAIV. Trial Registration ClinicalTrials.gov NCT00946101, NCT00945893

Duration of Protection Provided by Live Attenuated Influenza Vaccine in Children

Background: Reliable availability of influenza vaccine before October could enable the vaccination of many children who might not otherwise be vaccinated. Methods: Available data for children were analyzed to describe protection provided by live attenuated influenza vaccine (LAIV) for greater than 5 months postvaccination. Results: Four studies conducted in children aged 6 months to 18 years were identified. Culture-confirmed efficacy against A/H1N1 and A/H3N2 strains at 9–12 months postvaccination was 77% [95% confidence interval (CI): 53–89%] to 100% (95% CI: 68–100%) and through a second influenza season without revaccination was 56% (95% CI: 31–73%) and 57% (95% CI: 6–82%), respectively. Against B strains, 1 study demonstrated 86% (95% CI: 59–95%) efficacy at 5–7 months. Another study demonstrated 27% (95% CI: −62% to 67%) efficacy at 9–12 months compared with 74% (95% CI: 39–89%) at 1 to <5 months during a period of antigenic drift for circulating B strains. A third study estimated 50% (95% CI: −49% to 83%) efficacy against influenza B strains through a second season without revaccination. Conclusions: In children, live attenuated influenza vaccine provided sustained protection against influenza illness caused by antigenically similar strains. Efficacy at 1 to <5 months postvaccination was comparable to that at 9–12 months for A/H1N1 and A/H3N2 strains and at 5–7 months for B strains. Meaningful efficacy was seen through a second season without revaccination, although at a lower level than during the first 12 months postvaccination.

A randomized, double-blind noninferiority study of quadrivalent live attenuated influenza vaccine in adults ☆

BACKGROUND Trivalent seasonal influenza vaccines contain 2 A strains and 1 B strain. B strains of 2 antigenically distinct lineages, Yamagata and Victoria, have been co-circulating annually, and the B strain included in vaccines often has not been a lineage match to the major circulating strain. Thus, a vaccine containing B strains from both lineages could broaden protection against influenza. Quadrivalent live attenuated influenza vaccine (Q/LAIV) is an investigational 4-strain formulation of LAIV that contains 2 A strains, A/H1N1 and A/H3N2, and 2 B strains, 1 from each lineage. METHODS A randomized, double-blind, active-controlled study of Q/LAIV was conducted in 1800 adults aged 18-49 years to compare the immunogenicity and safety of Q/LAIV to trivalent LAIV (T/LAIV). Subjects were randomized 4:1:1 to receive an intranasal dose of Q/LAIV (n=1200) or 1 of 2 matching T/LAIV vaccines, each containing 1 of the B strains included in Q/LAIV (n=600 total). The primary endpoint was the comparison of the post-vaccination strain-specific geometric mean titers (GMT) of hemagglutination inhibition antibody in Q/LAIV recipients to those in T/LAIV recipients, with immunologic noninferiority of Q/LAIV to be demonstrated if the upper bound of the 2-sided 95% confidence interval (CI) for the ratio of the GMTs [T/LAIV divided by Q/LAIV] was ≤1.5 for all strains. RESULTS AND CONCLUSION Q/LAIV met the criteria for noninferiority: the ratios of the GMTs for the A/H1N1, A/H3N2, B/Yamagata, and B/Victoria strains were 1.09 (95% CI, 1.01-1.18), 1.05 (95% CI, 0.96-1.14), 1.10 (95% CI, 0.97-1.25), and 0.92 (95% CI, 0.82-1.03), respectively. Solicited symptoms and adverse events were similar in the Q/LAIV and T/LAIV arms. Q/LAIV may confer increased protection against influenza by targeting B strains from both lineages.

Efficacy of live attenuated influenza vaccine in children 6 months to 17 years of age.

Please cite this paper as: Belshe et al. (2010). Efficacy of live attenuated influenza vaccine in children 6 months to 17 years of age. Influenza and Other Respiratory Viruses 4(3), 141–145.

An integrated, multistudy analysis of the safety of Ann Arbor strain live attenuated influenza vaccine in children aged 2–17 years

Please cite this paper as: Ambrose et al. (2011) An integrated, multistudy analysis of the safety of Ann Arbor strain live attenuated influenza vaccine in children aged 2–17 years. Influenza and Other Respiratory Viruses 5(6), 389–397.

Anti-influenza serum and mucosal antibody responses after administration of live attenuated or inactivated influenza vaccines to HIV-infected children.

Background:Live-attenuated influenza vaccine (LAIV) prevents more cases of influenza in immune-competent children than the trivalent inactivated vaccine (TIV). We compared the antibody responses to LAIV or TIV in HIV-infected children. Methods:Blood and saliva obtained at enrollment, 4 and 24 weeks postimmunization from 243 HIV-infected children randomly assigned to TIV or LAIV were analyzed. Results:Both vaccines increased the anti-influenza neutralizing antibodies at 4 and 24 weeks postimmunization. At 4 weeks postimmunization, TIV recipients had 2-fold to 3-fold higher neutralizing antibody titers than LAIV recipients, but the proportions of subjects with protective titers (≥1:40) were similar between treatment groups (96%-100% for influenza A and 81%-88% for influenza B). Both vaccines increased salivary homotypic IgG antibodies, but not IgA antibodies. Both vaccines also increased serum heterosubtypic antibodies. Among HIV-specific characteristics, the baseline viral load correlated best with the antibody responses to either vaccine. We used LAIV-virus shedding as a surrogate of influenza infection. Influenza-specific humoral and mucosal antibody levels were significantly higher in nonshedders than in shedders. Conclusions:LAIV and TIV generated homotypic and heterosubtypic humoral and mucosal antibody responses in HIV-infected children. High titers of humoral or mucosal antibodies correlated with protection against viral shedding.