Altered Response to A(H1N1)pnd09 Vaccination in Pregnant Women: A Single Blinded Randomized Controlled Trial

<div><p>Background</p><p>Pregnant women were suspected to be at particular risk when H1N1pnd09 influenza became pandemic in 2009. Our primary objective was to compare the immune responses conferred by MF59®-adjuvanted vaccine (Focetria®) in H1N1pnd09-naïve pregnant and non-pregnant women. The secondary aims were to compare influences of dose and adjuvant on the immune response.</p><p>Methods</p><p>The study was nested in the Copenhagen Prospective Studies on Asthma in Childhood (COPSAC₂₀₁₀) pregnancy cohort in 2009-2010 and conducted as a single-blinded block-randomised [1∶1∶1] controlled clinical trial in pregnant women after gestational week 20: (1) 7.5 µg H1N1pnd09 antigen with MF59-adjuvant (Pa7.5 µg); (2) 3.75 µg antigen half MF59-adjuvanted (Pa3.75 µg); (3) 15 µg antigen unadjuvanted (P15 µg); and in non-pregnant women receiving (4) 7.5 µg antigen full adjuvanted (NPa7.5 µg). Blood samples were collected at baseline, 3 weeks, 3 and 10 months after vaccination, adverse events were recorded prospectively.</p><p>Results</p><p>58 pregnant women were allocated to Pa7.5 µg and 149 non-pregnant women were recruited to NPa7.5 µg. The sero-conversion rate was significantly increased in non-pregnant (NPa7.5 µg) compared with pregnant (Pa7.5 µg) women (OR = 2.48 [1.03–5.95], p = 0.04) and geometric mean titers trended towards being higher, but this difference was not statistically significant (ratio 1.27 [0.85–1.93], p = 0.23). The significant titer increase rate showed no difference between pregnant (Pa7.5 µg) and non-pregnant (NPa7.5 µg) groups (OR = 0.49 [0.13–1.85], p = 0.29).</p><p>Conclusion</p><p>Our study suggests the immune response to the 7.5 µg MF59-adjuvanted Focetria® <i>H1N1pnd09</i> vaccine in pregnant women may be diminished compared with non-pregnant women.</p><p>Trial Registration</p><p>ClinicalTrials.gov<a href="http://www.clinicaltrials.gov/ct2/show/NCT01012557?term=NCT01012557&rank=1" target="_blank"> NCT01012557</a>.</p></div

Study group flowchart.

<p>Study group flowchart.</p

Antibody responses according to vaccine groups.

<p>P: Pregnant.</p><p>NP: Non-pregnant.</p><p>GMT: Geometric mean titer.</p><p>GMR: Geometric mean ratio.</p><p>CI: Confidence interval.</p><p>Sero-protection: Titer ≥40.</p><p>Sero-conversion: Pre titer<10, Post titer ≥40.</p><p>Significant increase: Pre titer ≥10, Post titer 4 fold Pre titer.</p><p>Sero-conversion or significant increase: Percentage of total number of women in each vaccine group.</p>†<p>At day 0 GMT were the same in all groups (ANOVA, p = 0.51).</p>‡<p>The number of women with sero-protection did not differ in any of the groups compared over time (GEE).</p>*<p>GMT at 3 weeks, 3 months and 10 months were adjusted for baseline titer.</p

Evolution of sero-conversion rate (as percentage) in women in the four vaccine groups over time.

<p>The trends over time for the number of women sero-converted were not significantly different. The number of non-pregnant women (NPa7.5 µg) who sero-converted was 2.48-fold higher than among pregnant (Pa7.5 µg) women using general estimating equations.</p

Evolution of geometric mean titers in the four vaccine groups over time.

<p>The trends over time for geometric mean titers in the vaccine groups were not significantly different using general estimating equations.</p

Definitions.

<p>Definitions.</p

Baseline characteristic of the study subjects according to vaccine group.

A<p>ANOVA.</p>F<p>Fisher's exact test.</p>*<p>The gestational age at time of vaccination is different in the Pa3.75 µg group compared with the Pa7.5 µg group (P = 0.01). There is no significant difference between Pa7.5 µg and P15 µg (P = 0.82). Wilcoxon Rank Sum Test (t approximation).</p