Quadrivalent vs Trivalent Influenza Vaccines in Children
Quadrivalent vs Trivalent Influenza Vaccines in Children
A total of 599 children were enrolled in the study, of which all received at least 1 vaccination, and 584 completed the study (Trial Profile, Supplemental Digital Content 1, http://links.lww.com/INF/B972). In the primed cohort, 95 children received QIV and 97 received TIV, and in the unprimed cohort, 203 children received QIV and 204 received TIV. The median age of children in the total vaccinated cohort was 33.0 months (range: 18.0–47.0 months), and 52.4% were boys. The demographic characteristics were balanced across cohorts (Table 1). The study was performed in 2 centers in Mexico. The first child was enrolled in October 2009 and the last study visit was in May 2010.
Descriptive HI Antibody Responses in the Primed and Unprimed Cohorts. At Day 0, 56.8–63.8% of children in the primed cohort and 35.9–44.3% of children in the unprimed cohort were seropositive for influenza A strains (Fig. 1). At Day 0, 77.7–84.2% of children in the primed cohort and 23.9–28.8% of children in the unprimed cohort were seropositive for B/Yamagata, and 27.7–29.5% and 15.8–21.2% in the primed and unprimed cohort, respectively, were seropositive for B/Victoria.
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Figure 1.
HI seropositivity (titer ≥1:10) before vaccination on Day 0 in primed and unprimed children in the per-protocol immunogenicity cohort. CI, confidence interval; QIV, inactivated quadrivalent influenza vaccine, TIV, inactivated trivalent influenza vaccine; "Primed" and "unprimed," respectively, did and did not receive two doses of TIV in preceding season.
HI antibody GMTs by vaccine group stratified according to priming status are shown in Figure 2 and other parameters are shown in Table, Supplemental Digital Content 2, http://links.lww.com/INF/C9. After 1 dose of QIV or TIV, respectively, SCRs against A/H1N1 were 31.9% and 41.1% in the primed cohort, compared with 66.3% and 73.3% in the unprimed cohort. After 1 dose of QIV or TIV, respectively, SCRs against A/H3N2 were 51.1% and 48.4% in the primed cohort, compared with 57.3% and 54.0% in the unprimed cohort. After 1 dose of QIV or TIV, respectively, the SCRs against B/Yamagata were 87.2% and 42.1% in the primed cohort compared with 63.4% and 39.6% in the unprimed cohort, and SCRs against B/Victoria were 48.9% and 44.2% in the primed cohort, and 36.2% and 39.6% in the unprimed cohort. In the unprimed cohort, after 2 doses of TIV, the SCR and seroprotection rate against B/Yamagata (alternate-lineage strain) were 43.3% and 60.2%, respectively.
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Figure 2.
HI GMTs in primed and unprimed children in the per-protocol immunogenicity cohort. GMT, geometric mean titer; QIV, inactivated quadrivalent influenza vaccine; TIV, inactivated trivalent influenza vaccine.
The non-inferiority of adjusted GMTs was demonstrated for QIV versus TIV 28 days after the last vaccination in the primed and unprimed (Day 56 sub-cohort) cohorts pooled. The adjusted GMT ratio was 1.05 (95% CI: 0.84–1.33) against A/H1N1, 1.02 (95% CI: 0.85–1.23) against A/H3N2, and 1.05 (95% CI: 0.81–1.37) against B/Yamagata.
The superiority of adjusted GMTs was demonstrated for QIV versus TIV against B/Yamagata (alternate-lineage B strain) 28 days after the last vaccination in the primed and unprimed (Day 56 sub-cohort) cohorts pooled; the adjusted GMT ratio was 4.25 (95% CI: 3.47–5.21). After 1 dose of QIV, the adjusted GMTs in the primed cohort for A/H1N1, A/H3N2, B/Victoria and B/Yamagata were 117.0, 85.2, 38.7 and 243.6, respectively, and in the unprimed Day 28 sub-cohort were 173.1, 99.3, 26.5 and 97.0, respectively. The adjusted GMT ratio of primed/unprimed (Day 28 sub-cohort) children after 1 dose of QIV was 1.14 (0.74–1.76), which means that superiority was not demonstrated against B/Yamagata (homologous priming not superior to unprimed) (Fig. 3). However, because adjusting for baseline titer removes any effect of baseline titer (ie, priming effect), a post-hoc analysis with unadjusted GMTs was performed, and the GMT ratio was 2.51 (95% CI: 1.59–3.96), thus showing superiority of QIV in the primed versus unprimed children (Fig. 3). After 1 dose of QIV or TIV, the adjusted GMT ratio of primed (TIV and QIV pooled)/unprimed (QIV and TIV pooled) children against B/Victoria was 1.14 (95% CI: 0.86–1.50), and superiority was not demonstrated (heterologous priming not superior to unprimed); superiority was not shown in the post-hoc analysis of GMTs not adjusted for baseline titer.
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Figure 3.
HI GMT ratios for primed versus unprimed children against influenza B/Yamagata and B/Victoria after 1 dose of vaccine (Day 28) in the per-protocol immunogenicity cohort. HI, hemagglutination-inhibition; GMT, geometric mean titer; CI, confidence Interval; QIV, inactivated quadrivalent influenza vaccine; TIV, inactivated trivalent influenza vaccine; "Adjusted" GMT adjusted for baseline titer; "Unadjusted" GMT not adjusted for baseline titer; "Primed" and "unprimed," respectively, did and did not receive 2 doses of TIV in preceding season; In the primed cohort, antibody responses were assessed at Day 28; In the unprimed cohort, antibody responses were assessed in half of the population at Day 28 (after dose 1) and in the other half of the population at Day 56 (after dose 2).
A summary of solicited injection site and general AEs in each vaccine group (primed and unprimed pooled) is shown in Figure 4. In children who received QIV, solicited injection site reactions were reported in 39.3% (117/298) and 33.5% (66/197) after the first and second doses, respectively, compared with 35.9% (108/301) and 29.4% (59/201), respectively, in children who received TIV. In children who received QIV, Grade 3 injection site reactions were reported in 0.7% (2/298) and 1.0% (2/197) after the first and second doses, respectively, compared with none and 0.5% (1/201), respectively, in those who received TIV. The most frequent injection site event was pain with both vaccines, which was reported for 42.7% (125/293) of children who received QIV, and for 38.9% (116/298) of children who received TIV. Redness and swelling were reported for <11.4% of children with both vaccines.
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Figure 4.
Solicited local (A) and general (B) AEs in the total vaccinated cohort. †Oral/axillary temperature ≥37.5°C or a rectal temperature ≥38°C; Grade 3 fever, temperature >39°C; only children who did not receive TIV in the preceding season (unprimed) received dose 2.
In children who received QIV, solicited general AEs were reported for 46.6% (139/298) and 49.7% (98/197) of children after the first and second doses, respectively, compared with 44.9% (135/301) and 42.3% (85/201), respectively, in those who received TIV. Grade 3 solicited general AEs were reported for 1.7% (5/298) and 3.0% (6/197) of QIV recipients after the first and second doses, respectively, compared with 2.7% (8/301) and 0.5% (1/201) of TIV recipients, respectively. The most frequent general AEs were loss of appetite and irritability, which were reported for 30.4% (89/293) and 30.7% (90/293) of QIV recipients, respectively, and 28.9% (89/298) and 29.2% (87/298) of TIV recipients, respectively.
During the 28-day postvaccination period(s) with QIV, 38.9% (116/298), and with TIV, 39.2% (118/301) of children experienced at least 1 unsolicited AE, of which 3.4% (10/298) and 4.0% (12/301) with QIV and TIV, respectively, were Grade 3 events. Nasopharyngitis was the most frequent unsolicited AE, reported for 24.2% and 22.9% of QIV and TIV recipients, respectively. With QIV, there were 9 AEs in 7 children, and with TIV there were 9 AEs in 9 children that were considered by the investigator to have a causal relationship with vaccination, of which nasopharyngitis was the most common AE.
Over the 6-month study period, 2 children who received TIV experienced an SAE, which were: bronchopneumonia 87 days after the second dose of TIV, requiring hospitalization and resolving after 18 days; and urticaria 107 days after the second dose of TIV, requiring hospitalization and resolving after 6 days. None of these events were considered by the investigator to be vaccination related. No fatalities were reported.
Results
A total of 599 children were enrolled in the study, of which all received at least 1 vaccination, and 584 completed the study (Trial Profile, Supplemental Digital Content 1, http://links.lww.com/INF/B972). In the primed cohort, 95 children received QIV and 97 received TIV, and in the unprimed cohort, 203 children received QIV and 204 received TIV. The median age of children in the total vaccinated cohort was 33.0 months (range: 18.0–47.0 months), and 52.4% were boys. The demographic characteristics were balanced across cohorts (Table 1). The study was performed in 2 centers in Mexico. The first child was enrolled in October 2009 and the last study visit was in May 2010.
Immunogenicity
Descriptive HI Antibody Responses in the Primed and Unprimed Cohorts. At Day 0, 56.8–63.8% of children in the primed cohort and 35.9–44.3% of children in the unprimed cohort were seropositive for influenza A strains (Fig. 1). At Day 0, 77.7–84.2% of children in the primed cohort and 23.9–28.8% of children in the unprimed cohort were seropositive for B/Yamagata, and 27.7–29.5% and 15.8–21.2% in the primed and unprimed cohort, respectively, were seropositive for B/Victoria.
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Figure 1.
HI seropositivity (titer ≥1:10) before vaccination on Day 0 in primed and unprimed children in the per-protocol immunogenicity cohort. CI, confidence interval; QIV, inactivated quadrivalent influenza vaccine, TIV, inactivated trivalent influenza vaccine; "Primed" and "unprimed," respectively, did and did not receive two doses of TIV in preceding season.
HI antibody GMTs by vaccine group stratified according to priming status are shown in Figure 2 and other parameters are shown in Table, Supplemental Digital Content 2, http://links.lww.com/INF/C9. After 1 dose of QIV or TIV, respectively, SCRs against A/H1N1 were 31.9% and 41.1% in the primed cohort, compared with 66.3% and 73.3% in the unprimed cohort. After 1 dose of QIV or TIV, respectively, SCRs against A/H3N2 were 51.1% and 48.4% in the primed cohort, compared with 57.3% and 54.0% in the unprimed cohort. After 1 dose of QIV or TIV, respectively, the SCRs against B/Yamagata were 87.2% and 42.1% in the primed cohort compared with 63.4% and 39.6% in the unprimed cohort, and SCRs against B/Victoria were 48.9% and 44.2% in the primed cohort, and 36.2% and 39.6% in the unprimed cohort. In the unprimed cohort, after 2 doses of TIV, the SCR and seroprotection rate against B/Yamagata (alternate-lineage strain) were 43.3% and 60.2%, respectively.
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Figure 2.
HI GMTs in primed and unprimed children in the per-protocol immunogenicity cohort. GMT, geometric mean titer; QIV, inactivated quadrivalent influenza vaccine; TIV, inactivated trivalent influenza vaccine.
Non-inferiority and Superiority of HI Antibody Responses
The non-inferiority of adjusted GMTs was demonstrated for QIV versus TIV 28 days after the last vaccination in the primed and unprimed (Day 56 sub-cohort) cohorts pooled. The adjusted GMT ratio was 1.05 (95% CI: 0.84–1.33) against A/H1N1, 1.02 (95% CI: 0.85–1.23) against A/H3N2, and 1.05 (95% CI: 0.81–1.37) against B/Yamagata.
The superiority of adjusted GMTs was demonstrated for QIV versus TIV against B/Yamagata (alternate-lineage B strain) 28 days after the last vaccination in the primed and unprimed (Day 56 sub-cohort) cohorts pooled; the adjusted GMT ratio was 4.25 (95% CI: 3.47–5.21). After 1 dose of QIV, the adjusted GMTs in the primed cohort for A/H1N1, A/H3N2, B/Victoria and B/Yamagata were 117.0, 85.2, 38.7 and 243.6, respectively, and in the unprimed Day 28 sub-cohort were 173.1, 99.3, 26.5 and 97.0, respectively. The adjusted GMT ratio of primed/unprimed (Day 28 sub-cohort) children after 1 dose of QIV was 1.14 (0.74–1.76), which means that superiority was not demonstrated against B/Yamagata (homologous priming not superior to unprimed) (Fig. 3). However, because adjusting for baseline titer removes any effect of baseline titer (ie, priming effect), a post-hoc analysis with unadjusted GMTs was performed, and the GMT ratio was 2.51 (95% CI: 1.59–3.96), thus showing superiority of QIV in the primed versus unprimed children (Fig. 3). After 1 dose of QIV or TIV, the adjusted GMT ratio of primed (TIV and QIV pooled)/unprimed (QIV and TIV pooled) children against B/Victoria was 1.14 (95% CI: 0.86–1.50), and superiority was not demonstrated (heterologous priming not superior to unprimed); superiority was not shown in the post-hoc analysis of GMTs not adjusted for baseline titer.
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Figure 3.
HI GMT ratios for primed versus unprimed children against influenza B/Yamagata and B/Victoria after 1 dose of vaccine (Day 28) in the per-protocol immunogenicity cohort. HI, hemagglutination-inhibition; GMT, geometric mean titer; CI, confidence Interval; QIV, inactivated quadrivalent influenza vaccine; TIV, inactivated trivalent influenza vaccine; "Adjusted" GMT adjusted for baseline titer; "Unadjusted" GMT not adjusted for baseline titer; "Primed" and "unprimed," respectively, did and did not receive 2 doses of TIV in preceding season; In the primed cohort, antibody responses were assessed at Day 28; In the unprimed cohort, antibody responses were assessed in half of the population at Day 28 (after dose 1) and in the other half of the population at Day 56 (after dose 2).
Reactogenicity and Safety
A summary of solicited injection site and general AEs in each vaccine group (primed and unprimed pooled) is shown in Figure 4. In children who received QIV, solicited injection site reactions were reported in 39.3% (117/298) and 33.5% (66/197) after the first and second doses, respectively, compared with 35.9% (108/301) and 29.4% (59/201), respectively, in children who received TIV. In children who received QIV, Grade 3 injection site reactions were reported in 0.7% (2/298) and 1.0% (2/197) after the first and second doses, respectively, compared with none and 0.5% (1/201), respectively, in those who received TIV. The most frequent injection site event was pain with both vaccines, which was reported for 42.7% (125/293) of children who received QIV, and for 38.9% (116/298) of children who received TIV. Redness and swelling were reported for <11.4% of children with both vaccines.
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Figure 4.
Solicited local (A) and general (B) AEs in the total vaccinated cohort. †Oral/axillary temperature ≥37.5°C or a rectal temperature ≥38°C; Grade 3 fever, temperature >39°C; only children who did not receive TIV in the preceding season (unprimed) received dose 2.
In children who received QIV, solicited general AEs were reported for 46.6% (139/298) and 49.7% (98/197) of children after the first and second doses, respectively, compared with 44.9% (135/301) and 42.3% (85/201), respectively, in those who received TIV. Grade 3 solicited general AEs were reported for 1.7% (5/298) and 3.0% (6/197) of QIV recipients after the first and second doses, respectively, compared with 2.7% (8/301) and 0.5% (1/201) of TIV recipients, respectively. The most frequent general AEs were loss of appetite and irritability, which were reported for 30.4% (89/293) and 30.7% (90/293) of QIV recipients, respectively, and 28.9% (89/298) and 29.2% (87/298) of TIV recipients, respectively.
During the 28-day postvaccination period(s) with QIV, 38.9% (116/298), and with TIV, 39.2% (118/301) of children experienced at least 1 unsolicited AE, of which 3.4% (10/298) and 4.0% (12/301) with QIV and TIV, respectively, were Grade 3 events. Nasopharyngitis was the most frequent unsolicited AE, reported for 24.2% and 22.9% of QIV and TIV recipients, respectively. With QIV, there were 9 AEs in 7 children, and with TIV there were 9 AEs in 9 children that were considered by the investigator to have a causal relationship with vaccination, of which nasopharyngitis was the most common AE.
Over the 6-month study period, 2 children who received TIV experienced an SAE, which were: bronchopneumonia 87 days after the second dose of TIV, requiring hospitalization and resolving after 18 days; and urticaria 107 days after the second dose of TIV, requiring hospitalization and resolving after 6 days. None of these events were considered by the investigator to be vaccination related. No fatalities were reported.
