Altered response to A(H1N1)pnd09 vaccination in pregnant women: a single blinded randomized controlled trial

Anne Louise Bischoff, Nilofar Vahman Følsgaard, Charlotte Giwercman Carson, Jakob Stokholm, Louise Pedersen, Maria Holmberg, Amalie Bisgaard, Sune Birch, Theodore F Tsai, Hans Bisgaard, Anne Louise Bischoff, Nilofar Vahman Følsgaard, Charlotte Giwercman Carson, Jakob Stokholm, Louise Pedersen, Maria Holmberg, Amalie Bisgaard, Sune Birch, Theodore F Tsai, Hans Bisgaard

Abstract

Background: 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.

Methods: 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.

Results: 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).

Conclusion: Our study suggests the immune response to the 7.5 µg MF59-adjuvanted Focetria® H1N1pnd09 vaccine in pregnant women may be diminished compared with non-pregnant women.

Trial registration: ClinicalTrials.gov NCT01012557.

Conflict of interest statement

Competing Interests: TFT is employed by Novartis Vaccines. The nested vaccine study is funded by Novartis Vaccines and Diagnostics GmbH, Marburg, Germany, who provided vaccines and funding as an unrestricted institutional grant. The main Copenhagen Prospective Study on Asthma in Childhood birth cohort study is funded by private and public research funds (see www.copsac.com). There are no further patents, products in development or marketed products to declare. This does not alter the authors' adherence to all the PLOS ONE policies on sharing data and materials, as detailed online in the guide for authors.

Figures

Figure 1. Study group flowchart.
Figure 1. Study group flowchart.
Figure 2. Evolution of geometric mean titers…
Figure 2. Evolution of geometric mean titers in the four vaccine groups over time.
The trends over time for geometric mean titers in the vaccine groups were not significantly different using general estimating equations.
Figure 3. Evolution of sero-conversion rate (as…
Figure 3. Evolution of sero-conversion rate (as percentage) in women in the four vaccine groups over time.
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.

References

    1. Neuzil KM, Reed GW, Mitchel EF, Simonsen L, Griffin MR (1998) Impact of Influenza on Acute Cardiopulmonary Hospitalizations in Pregnant Women. American Journal of Epidemiology 148: 1094 –1102.
    1. Blanchard-Rohner G, Siegrist C-A (2011) Vaccination during pregnancy to protect infants against influenza: why and why not? Vaccine 29: 7542–7550 doi:.
    1. Skowronski DM, De Serres G (2009) Is routine influenza immunization warranted in early pregnancy? Vaccine 27: 4754–4770 doi:.
    1. Harris JW (1919) Influenza Occurring in Pregnant Women. The Journal of the American Medical Association 72: 978 –980. doi:10.1001/jama.1919.02610140008002.
    1. Freeman DW, Barno A (1959) Deaths from Asian Influenza Associated with Pregnancy. Am J Obstet Gynecol 78: 1172–1175.
    1. Strategic Advisory Group of Experts on Immunization - report of the extraordinary meeting on the influenza A (H1N1) 2009 pandemic, 7 July 2009 (2009) Wkly Epidemiol Rec. 84: 301–304.
    1. Luteijn JM, Dolk H, Marnoch GJ (2011) Differences in pandemic influenza vaccination policies for pregnant women in Europe. BMC Public Health 11: 819 doi:.
    1. Siston AM, Rasmussen SA, Honein MA, Fry AM, Seib K, et al. (2010) Pandemic 2009 influenza A(H1N1) virus illness among pregnant women in the United States. JAMA 303: 1517–1525 doi:.
    1. Yates L, Pierce M, Stephens S, Mill AC, Spark P, et al. (2010) Influenza A/H1N1v in pregnancy: an investigation of the characteristics and management of affected women and the relationship to pregnancy outcomes for mother and infant. Health Technol Assess 14: 109–182 doi:.
    1. Critical illness due to 2009 A/H1N1 influenza in pregnant and postpartum women: population based cohort study (2010) BMJ. 340: c1279.
    1. Pierce M, Kurinczuk JJ, Spark P, Brocklehurst P, Knight M, et al. (2011) Perinatal outcomes after maternal 2009/H1N1 infection: national cohort study. BMJ 342: d3214–d3214 doi:.
    1. Jamieson DJ, Theiler RN, Rasmussen SA (2006) Emerging infections and pregnancy. Emerging Infect Dis 12: 1638–1643.
    1. Tamma PD, Ault KA, Del Rio C, Steinhoff MC, Halsey NA, et al. (2009) Safety of influenza vaccination during pregnancy. Am J Obstet Gynecol 201: 547–552 doi:.
    1. Mak TK, Mangtani P, Leese J, Watson JM, Pfeifer D (2008) Influenza vaccination in pregnancy: current evidence and selected national policies. The Lancet Infectious Diseases 8: 44–52 doi:.
    1. Hulka JF (1964) Effectiveness of Polyvalent Influenza Vaccine in Pregnancy. Report of a Controlled Study During an Outbreak of Asian Influenza. Obstet Gynecol 23: 830–837.
    1. Murray DL, Imagawa DT, Okada DM, St Geme JW Jr (1979) Antibody response to monovalent A/New Jersey/8/76 influenza vaccine in pregnant women. J Clin Microbiol 10: 184–187.
    1. Schlaudecker EP, McNeal MM, Dodd CN, Ranz JB, Steinhoff MC (2012) Pregnancy modifies the antibody response to trivalent influenza immunization. J Infect Dis 206: 1670–1673 doi:.
    1. Nasidi A, Monath TP, Vandenberg J, Tomori O, Calisher CH, et al. (1993) Yellow fever vaccination and pregnancy: a four-year prospective study. Trans R Soc Trop Med Hyg 87: 337–339.
    1. Schulz KF, Altman DG, Moher D (2010) For the CONSORT Group (2010) CONSORT 2010 Statement: updated guidelines for reporting parallel group randomised trials. BMJ 340: c332–c332 doi:.
    1. Følsgaard NV, Chawes BL, Rasmussen MA, Bischoff AL, Carson CG, et al... (2012) Neonatal Cytokine Profile in the Airway Mucosal Lining Fluid Is Skewed by Maternal Atopy. Am J Respir Crit Care Med 185: 275 –280. doi:10.1164/rccm.201108-1471OC.
    1. Hatz C, Von Sonnenburg F, Casula D, Lattanzi M, Leroux-Rouel G (n.d.) Randomized Clinical Trial to Identify the optimal Antigen and MF59 Adjuvant Dose of a Monovalent a/H1N1 Pandemic Influenza Vaccine in Adults and Elderly Subjects. in press.
    1. Gasparini R, Schioppa F, Lattanzi M, Barone M, Casula D, et al. (2010) Impact of prior or concomitant seasonal influenza vaccination on MF59-adjuvanted H1N1v vaccine (Focetria) in adult and elderly subjects. Int J Clin Pract 64: 432–438 doi:.
    1. Palmer DF, Dowle WR, Coleman MT, Schild GC (1975) Procedural guide. Part 2 haemagglutination – inhibition test. Advanced laboratory technicals for immunological diagnostic. U.S Dept. Hlth. Ed. Welfare, P.H.S. Atlanta, Immunology ser., Vol. 1975: 25–62.
    1. Katz J, Hancock K, Veguilla V, Zhong W, Lu X, et al. (2009) Serum cross-reactive antibody response to a novel influenza A (H1N1) virus after vaccination with seasonal influenza vaccine. MMWR Morb Mortal Wkly Rep 58: 521–524.
    1. Guideline On Dossier Structure And Content For Pandemic Influenza Vaccine Marketing Authorisation Application (Revision). (2008). Available: .Accessed 2012 Aug 29.
    1. Rowe T, Abernathy RA, Hu-Primmer J, Thompson WW, Lu X, et al. (1999) Detection of Antibody to Avian Influenza A (H5N1) Virus in Human Serum by Using a Combination of Serologic Assays. J Clin Microbiol 37: 937–943.
    1. Stephenson I, Bugarini R, Nicholson KG, Podda A, Wood JM, et al... (2005) Cross-Reactivity to Highly Pathogenic Avian Influenza H5N1 Viruses after Vaccination with Nonadjuvanted and MF59-Adjuvanted Influenza A/Duck/Singapore/97 (H5N3) Vaccine: A Potential Priming Strategy. Journal of Infectious Diseases 191: 1210 –1215. doi:10.1086/428948.
    1. O'Hagan DT, Rappuoli R, De Gregorio E, Tsai T, Del Giudice G (2011) MF59 adjuvant: the best insurance against influenza strain diversity. Expert Rev Vaccines 10: 447–462 doi:.
    1. Clark TW, Pareek M, Hoschler K, Dillon H, Nicholson KG, et al. (2009) Trial of 2009 Influenza A (H1N1) Monovalent MF59-Adjuvanted Vaccine. New England Journal of Medicine 361: 2424–2435 doi:.
    1. Fisher BM, Van Bockern J, Hart J, Lynch AM, Winn VD, et al. (2012) Pandemic Influenza A H1N1 2009 Infection versus Vaccination: A Cohort Study Comparing Immune Responses in Pregnancy. PLoS ONE 7: e33048 doi:.
    1. Zuccotti G PL (2010) TRansplacental antibody transfer following maternal immunization with a pandemic 2009 influenza a(h1n1) mf59-adjuvanted vaccine. JAMA 304: 2360–2361 doi:.
    1. Maternal Immune Response and Neonatal Seroprotection From a Single Dose of a Monovalent Nonadjuvanted 2009 Influenza A(H1N1) Vaccine (2011) Annals of Internal Medicine. 155: 733–741.
    1. Jackson LA, Patel SM, Swamy GK, Frey SE, Creech CB, et al. (2011) Immunogenicity of an inactivated monovalent 2009 H1N1 influenza vaccine in pregnant women. J Infect Dis 204: 854–863 doi:.
    1. Zaman K, Roy E, Arifeen SE, Rahman M, Raqib R, et al. (2008) Effectiveness of Maternal Influenza Immunization in Mothers and Infants. New England Journal of Medicine 359: 1555–1564 doi:.
    1. Puleston RL, Bugg G, Hoschler K, Konje J, Thornton J, et al. (2010) Observational study to investigate vertically acquired passive immunity in babies of mothers vaccinated against H1N1v during pregnancy. Health Technol Assess 14: 1–82 doi:.
    1. Eick AA, Uyeki TM, Klimov A, Hall H, Reid R, et al. (2011) Maternal influenza vaccination and effect on influenza virus infection in young infants. Arch Pediatr Adolesc Med 165: 104–111 doi:.
    1. Brent RL (2006) Risks and benefits of immunizing pregnant women: the risk of doing nothing. Reprod Toxicol 21: 383–389 doi:.
    1. Poehling KA, Szilagyi PG, Staat MA, Snively BM, Payne DC, et al. (2011) Impact of maternal immunization on influenza hospitalizations in infants. American Journal of Obstetrics and Gynecology 204: S141–S148 doi:.
    1. Heikkinen T, Young J, Van Beek E, Franke H, Verstraeten T, et al. (2012) Safety of MF59-adjuvanted A/H1N1 influenza vaccine in pregnancy: a comparative cohort study. Am J Obstet Gynecol 207: 177.e1–8 doi:.
    1. Fell DB, Sprague AE, Liu N, Yasseen AS 3rd, Wen S-W, et al (2012) H1N1 influenza vaccination during pregnancy and fetal and neonatal outcomes. Am J Public Health 102: e33–40 doi:.
    1. Shieh W-J, Blau DM, Denison AM, DeLeon-Carnes M, Adem P, et al. (2010) 2009 Pandemic Influenza A (H1N1). Am J Pathol 177: 166–175 doi:.
    1. Malek A, Sager R, Kuhn P, Nicolaides KH, Schneider H (1996) Evolution of maternofetal transport of immunoglobulins during human pregnancy. Am J Reprod Immunol 36: 248–255.
    1. Fox KA, Theiler R (2011) Vaccination in pregnancy. Curr Pharm Biotechnol 12: 789–796.
    1. Yamaguchi K, Hisano M, Isojima S, Irie S, Arata N, et al. (2009) Relationship of Th1/Th2 cell balance with the immune response to influenza vaccine during pregnancy. J Med Virol 81: 1923–1928 doi:.
    1. Challis JR, Lockwood CJ, Myatt L, Norman JE, Strauss JF, et al... (2009) Inflammation and Pregnancy. Reproductive Sciences 16: 206 –215. doi:10.1177/1933719108329095.
    1. Qin L, Gilbert PB, Corey L, McElrath MJ, Self SG (2007) A framework for assessing immunological correlates of protection in vaccine trials. J Infect Dis 196: 1304–1312 doi:.
    1. Coudeville L, Bailleux F, Riche B, Megas F, Andre P, et al. (2010) Relationship between haemagglutination-inhibiting antibody titres and clinical protection against influenza: development and application of a bayesian random-effects model. BMC Med Res Methodol 10: 18 doi:.
    1. Naleway AL, Smith WJ, Mullooly JP (2006) Delivering Influenza Vaccine to Pregnant Women. Epidemiologic Reviews 28: 47 –53. doi:10.1093/epirev/mxj002.
    1. Ohfuji S, Fukushima W, Deguchi M, Kawabata K, Yoshida H, et al. (2011) Immunogenicity of a Monovalent 2009 Influenza A (H1N1) Vaccine Among Pregnant Women: Lowered Antibody Response by Prior Seasonal Vaccination. J Infect Dis 203: 1301–1308 doi:.
    1. Partridge J, Kieny MP (2010) Global production of seasonal and pandemic (H1N1) influenza vaccines in 2009-2010 and comparison with previous estimates and global action plan targets. Vaccine 28: 4709–4712 doi:.
    1. Pasternak B SH (2012) RIsk of adverse fetal outcomes following administration of a pandemic influenza a(h1n1) vaccine during pregnancy. JAMA 308: 165–174 doi:.
    1. Lancaster PAL (2011) Causes of birth defects: Lessons from history. Congenital Anomalies 51: 2–5 doi:.
    1. Oster ME, Riehle-Colarusso T, Alverson CJ, Correa A (2011) Associations Between Maternal Fever and Influenza and Congenital Heart Defects. The Journal of Pediatrics 158: 990–995 doi:.
    1. Atladóttir HÓ, Henriksen TB, Schendel DE, Parner ET (2012) Autism After Infection, Febrile Episodes, and Antibiotic Use During Pregnancy: An Exploratory Study. Pediatrics. doi:10.1542/peds.2012-1107.

Source: PubMed

Sponzoři a spolupracovníci

Zdravotní podmínky

Drogové intervence

3
Předplatit