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Protective antibody responses to influenza A/H1N1/09 vaccination in children with celiac disease

SCHÄPPI, Michela G., et al.

Abstract

Patients with celiac disease have an increased risk for severe influenza infection and they show less of a response to certain vaccine types. During the influenza A/H1N1/09 pandemic, we prospectively investigated pandemic vaccine responses in 14 pediatric patients with celiac disease and age-/sex-matched controls. All of the children with celiac disease reached protective antibody titers (≥40) and showed a geometric mean titer comparable with the control group (530 vs 573).

SCHÄPPI, Michela G., et al . Protective antibody responses to influenza A/H1N1/09 vaccination in children with celiac disease. Journal of Pediatric Gastroenterology and Nutrition , 2012, vol. 54, no. 6, p. 817-9

DOI : 10.1097/MPG.0b013e318248e7be PMID : 22228003

Available at:

http://archive-ouverte.unige.ch/unige:29209

Disclaimer: layout of this document may differ from the published version.

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Copyright 2012 by ESPGHAN and NASPGHAN. Unauthorized reproduction of this article is prohibited.

Protective Antibody Responses to Influenza A/H1N1/09 Vaccination in Children With Celiac Disease

Michela G. Scha¨ppi, Sara Meier, Michael Bel, Claire-Anne Siegrist, and Klara M. Posfay-Barbe, on Behalf of the H1N1 Study Group

ABSTRACT

Patients with celiac disease have an increased risk for severe influenza infection and they show less of a response to certain vaccine types. During the influenza A/H1N1/09 pandemic, we prospectively investigated pan- demic vaccine responses in 14 pediatric patients with celiac disease and age-/sex-matched controls. All of the children with celiac disease reached protective antibody titers (40) and showed a geometric mean titer com- parable with the control group (530 vs 573).

Key Words:celiac disease, children, influenza, responder, vaccination (JPGN2012;54: 817–819)

C

hildren with celiac disease (CD) have an increased risk for influenza infection and secondary hospital admission (1). In addition, patients with CD seem to have weaker humoral responses to certain immunizations, such as hepatitis B vaccine (HBV) (2,3).

To our knowledge, no data describe the response of patients with CD to influenza vaccination. The emergence of the pandemic influenza A/H1N1/09 strain presented an opportunity to investigate vaccine responses in immunologically naı¨ve patients.

METHODS

We conducted a prospective open-label field study between November and February 2009–2010, recruiting a total of 86 children, including 14 with proven CD (serology and biopsy) and 14 sex- and age-matched immunocompetent controls (4). Blood was collected at baseline (optional) and 4 to 7 weeks postvaccina- tion. Vaccines administered were 2 monovalent, split-virion, squa- lene-adjuvanted vaccines containing H1N1 A/California/7/2009 X-179A: Pandemrix (GlaxoSmithKline, Rixensart, Belgium) or Focetria (Novartis, Sienna, Italy), according to official guidelines.

Antibody (AB) titers were measured by hemagglutination inhibition (HAI) and microneutralization (MN) in the laboratory of the Center for Vaccinology-Neonatal Immunology, Geneva, Switzerland. An HAI titer of40 was considered protective as previously described.

Presently, no protective thresholds are defined for MN titers.

Geometric mean titers (GMT) were calculated to compare average pre- and postvaccination titers. The present study was approved by the institutional ethics committee of the University Hospitals of Geneva and the Swiss Agency for Therapeutic Products (Swissmedic, Hallerstrasse, Switzerland); it was registered on www.clinicaltrials.govbefore patient recruitment.

RESULTS

The mean age of 14 white children with CD was 12.9 years (interquartile range [IQR] 9.8–15.9 years), and that of 14 age- and sex-matched controls was 12.0 years (IQR 8.2–14.4 years). Their baseline characteristics are presented in Table 1. Average age at diagnosis of CD was 3.8 years (IQR 1.2–5.1 years), and average time since diagnosis was 9.1 years (IQR 5.3–13.5 years). The majority of patients were girls (N¼9, 64%). Four of the children with CD (29%) had a positive serum anti-tissue transglutaminase (tTG) immunoglobulin (Ig) A concentration, suggesting possible noncompliance with a gluten-free diet. Human leukocyte antigen (HLA) typing was available for all 14 children: 7 (50%) were heterozygous and 7 were homozygous for HLA-DQ2. At baseline, HAI-GMT (available for 6 children with CD) was 39 (95% con- fidence interval [CI] 8%–197%); 3 children (50%) showed pro- tective titers (40), suggesting possible earlier exposure to the virus. Among controls, prevaccination blood samples were avail- able for 11 children. HAI-GMT was 17.2 (95% CI 7%–44%), and 3 children (27%) showed protective AB titers.

The responses to influenza A/H1N1/09 vaccination are represented in Table 1. All 28 children reached protective AB titers postvaccination. Among children with CD, HAI-GMT was 530 (95% CI 333%–842%) and MN-GMT was 488 (95% CI 253%–

939%). A good correlation between the 2 laboratory measurements (R2¼0.96, for postvaccination titers) confirmed reliable laboratory methods. Age-/sex-matched controls reached slightly higher but not significantly different GMT (HAI-GMT 573, 95% CI 369%–890%, Received October 14, 2011; accepted December 28, 2011.

From the Department of Pediatrics, University Hospitals of Geneva, Geneva, Switzerland.

Address correspondence and reprint requests to Dr Michela Scha¨ppi Tempia, MD, PD, Pediatric Gastroenterology Unit, Children’s Hospital of Geneva, 6, rue Willy-Donze´, 1211 Geneva 14, Switzerland (e-mail:

Michela.Tempia-Caliera@hcuge.ch).

Drs Michela G. Scha¨ppi and Sara Meier share first authorship.

This work was supported by an institutional grant of the Clinical Research Center of the University Hospitals of Geneva and Medical Faculty of Geneva and by the Center of Vaccinology.

www.clinicaltrials.govregistration number: NCT01022905.

The H1N1 study group of the Geneva University Hospitals, Geneva, Switzer- land: C.-A. Siegrist, K. Posfay-Barbe, S. Meier, M. Bel, S. Grillet, G.

Sealy: Center for Vaccinology; J. Demeules, S. Charvat, M. Verdon, C.

Combescure: Clinical Research Center; B. Hirschel, A. Calmy, A.

Nguyen, C. Delhumeau-Cartier, J. Ambrosioni: Division of Infectious Diseases; C. Gabay, P.A. Guerne: Division of Rheumatology; J. Seebach, C. Ribi, J. Villard: Division of Immunology and Allergology; P.Y.

Dietrich, A.C. George, L. Favet: Division of Oncology; C. van Delden, I. Morard, G. Mentha, E. Giostra: Division of Transplantation; K.

Hadaya, P.Y. Martin: Division of Nephrology; P. Soccal: Division of Thoracic Surgery; T. Berney: Division of Visceral surgery; S. Noble:

Division of Cardiology; B. Mohty, M. Nagy, Y. Chalandon, E. Roosnek, J. Passweg: Division of Hematology; L. Kaiser, S. Yerly, Y. Thomas, W.

Wunderli: Laboratory of Virology; D. Belli: Department of Pediatrics.

The authors report no conflicts of interest.

Copyright# 2012 by European Society for Pediatric Gastroenterology, Hepatology, and Nutrition and North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition

DOI: 10.1097/MPG.0b013e318248e7be

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OMMUNICATION

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Copyright 2012 by ESPGHAN and NASPGHAN. Unauthorized reproduction of this article is prohibited.

TABLE1.BaselinecharacteristicsandresponsestoinfluenzaA/H1N1/09vaccinationin14childrenwithceliacdisease(ingray)andoftheirage-/sex-matchedcontrols (inwhite) Sex

Ageat vaccination, y

Ageat diagnosis, y

Timesince diagnosis, y Anti-tTG IgA(around vaccination)HLA-DQ2 typing

ILIsince summer 2009

ILIto vaccination, dVaccine type Vaccineto sampling, wk BaselineHAI anti-H1N1 ABtitery

PostvacHAI anti-H1N1 ABtitery

PostvacMN anti-H1N1 ABtiter

Fold-increase (post-/pre-HAI titers) F5.25.00.2154z Heteroyes13F5.9201240 F4.1noF10.1512560 F13.311.51.880HeteronoP7.0425696064 F12.7noF4.41324582560184 F13.21.212.06HeteronoP4.91111951280109 F14.1noF4.442139803 M7.31.85.56HomonoP4.31281609256013 M6.6noP6.1423016058 M9.31.87.533z HeteronoF4.3128240 M8.3noP6.3618314031 M14.20.813.46HeteronoP4.01024153625602 M13.3noF4.36683960114 M17.81.016.820HomonoP4.353128802 M17.3yes3F10.36401280 M14.29.54.72HomonoF3.933380 M13.8noF5.0683184351203 F16.43.013.42HeteronoF3.91229640 F14.3noP5.06467264011 F12.35.56.824z HeteronoP5.0123846032 F14.0noP5.116683160043 F18.44.513.911HomonoP5.16141280 F14.5noF9.0423032058 F21.12.518.619HomonoP5.1805640 F15.0noF8.17681280 F11.34.07.39HomonoP5.9922960 F11.5noF3.05768320144 F6.71.05.718Homoyes12F8.0768480 F7.8noP5.036110964031 AB¼antibody;F¼focetria;HAI¼hemagglutinationinhibition;IgG¼immunoglobulinG;ILI¼influenza-likeillness;MN¼microneutralization;NA¼notapplicable;P¼pandemrix;tTG¼tissue transglutaminaseantibodies. Eachlinedescribingacase(ingray)isfollowedbyitscorrespondingcontrol(inwhite). yAnHAItiterof40isconsideredprotective. z Valuesabovethresholdof20IU.

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Copyright 2012 by ESPGHAN and NASPGHAN. Unauthorized reproduction of this article is prohibited.

P¼0.812; MN-GMT 625, 95% CI 339%–1153%, P¼0.592).

Among children with CD, HAI titer was significantly dependent on dietary compliance (HAI-GMT of 4 children with anti-tTG IgA levels >20 IU around time of vaccination: 224, 95% CI 143%–352%; HAI-GMT of 10 children with anti-tTG IgA levels

<20 IU around time of vaccination: 747, 95% CI 461%–1209%, P¼0.028). HAI titer was not dependent on HLA status (HAI-GMT for HLA-DQ2 heterozygotes: 478, 95% CI 228%–1004%;

HAI-GMT for HLA-DQ2 homozygotes: 587, 95% CI 320%–

1078%;P¼0.798).

DISCUSSION

Children with CD can produce antibodies following influ- enza A/H1N1/09 vaccination, with GMT clearly above the protec- tive threshold. This is important because data concerning AB responses of patients with CD to other vaccine types remain contradictory. Certain studies have reported diminished responses of patients with CD to HBV, and attributed this to HLA-DQ2, -DR3, and -DR7 serotypes (2,3). These serotypes (particularly DQ2) are strongly associated with CD, and have been independently linked to the nonresponse to HBV, especially if present in homozygous form (2,3). In our study, DQ2 homozygotes responded equally well as heterozygotes; therefore, we cannot confirm any hypothesis linking diminished immune responses to the DQ2 zygosity. Other studies have shown a good response of patients with CD to HBV if a strict gluten-free diet was followed and low disease-activity markers were present (eg, serum titers of anti-tissue transglutaminase antibodies) (5), suggesting that genetic factors play a subordinate role to environmental ones. In our study, the 4 children with high anti- tTG levels (therefore considered less compliant with gluten-free diet) did in fact reach significantly lower titers than children who were fully compliant. Competition between H1N1 protein frag- ments and gliadin peptides to bind to HLA-DQ2 molecules may result in a defective AB response in noncompliant children (6);

however, all 3 children with possible pre-exposure to the H1N1 virus were part of the diet-compliant group, which may have led to the overestimation of vaccine effect in that group.

Regarding present evidence on other vaccine types, response rates to pneumococcal (7), rubella (2), andHaemophilus influenza type b (2) vaccines seem to be similar in patients with CD and controls. Evidence about tetanus vaccine is conflicting (2,8), and immune responses to oral polio vaccine may be stronger in patients with CD (9).

The limitations of our study include small sample size, mainly due to Swiss parents’ general resistance to H1N1 vaccina- tion and the overlapping of vaccination with the peak of the epidemic due to delayed national vaccines’ availability leading to possible overestimation of the vaccine effect. Due to widespread parental apprehension, baseline AB sampling was not possible for all children, making accurate estimation of baseline titers difficult.

Furthermore, 2 vaccines were used because of changing official recommendations; however, in our larger-scale study including more children, they were shown to be equally immunogenic (4).

CONCLUSIONS

In spite of its limitations, the key message of the present study remains strong and valid: pediatric patients with CD respond well to influenza vaccination and this can be used to help limit the particular risk of influenza complications in this population.

REFERENCES

1. Marild K, Fredlund H, Ludvigsson JF. Increased risk of hospital admission for influenza in patients with celiac disease: a nation- wide cohort study in Sweden. Am J Gastroenterol2010;105:2465–

2473.

2. Park SD, Markowitz J, Pettei M, et al. Failure to respond to hepatitis B vaccine in children with celiac disease.J Pediatr Gastroenterol Nutr 2007;44:431–5.

3. Zingone F, Morisco F, Zanetti A, et al. Long-term antibody persistence and immune memory to hepatitis B virus in adult celiac patients vaccinated as adolescents.Vaccine2011;29;29:1005–8.

4. Meier S, Bel M, L’huillier A, et al. Antibody responses to natural influenza A/H1N1/09 disease or following immunization with adjuvanted vaccines, in immunocompetent and immunocompromised children.

Vaccine2011;29:3548–57.

5. Ertem D, Gonen I, Tanidir C, et al. The response to hepatitis B vaccine:

does it differ in celiac disease? Eur J Gastroenterol Hepatol2010;

22:787–93.

6. Nemes E, Lefler E, Szegedi L, et al. Gluten intake interferes with the humoral immune response to recombinant hepatitis B vaccine in patients with celiac disease.Pediatrics2008;121:e1570–6.

7. McKinley M, Leibowitz S, Bronzo R, et al. Appropriate response to pneumococcal vaccine in celiac sprue. J Clin Gastroenterol 1995;

20:113–6.

8. Pettingale KW. Immunoglobulin and specific antibody responses to antigenic stimulation in adult coeliac disease.Clin Sci1970;38:16.

9. Mawhinney H, Love AH. The immunoglobulin class responses to oral poliovaccine in coeliac disease.Clin Exp Immunol1975;21:399–406.

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