The German Infant Nutritional Intervention (GINI) study and formulation issues
Authors: James Vincent Meaney
Journal: Journal of Allergy and Clinical Immunology (2013)

In the recently published 10-year follow-up of the German Infant Nutritional Intervention (GINI) study, it is reported that partially hydrolyzed whey formula (pHF-W) and extensively hydrolyzed casein formula (eHF-C), but not extensively hydrolyzed whey formula (eHF-W), prevent allergic disease compared with standard cow's milk formula.1von Berg A. Filipiak-Pittroff B. Krämer U. Hoffmann B. Link E. Beckmann C. et al.Allergies in high-risk schoolchildren after early intervention with cow's milk protein hydrolysates: 10-year results from the German Infant Nutritional Intervention (GINI) study.J Allergy Clin Immunol. 2013; 131: 1565-1573Abstract Full Text Full Text PDF PubMed Scopus (141) Google Scholar These results suggest that both protein source and peptide size are important, and hence being able to identify studied formulas with marketed products and evaluating changes to formulations are crucial.2Scientific Committee on FoodReport of the Scientific Committee on Food on the revision of essential requirements of infant formulae and follow-on formulae. European Commission, Brussels2003Google Scholar In the case of the pHF-W and eHF-C used in the GINI study, some formulation changes since study enrollment ended in 1998 are noted, but it is reported that the "quality of the hydrolysates remained unchanged."1von Berg A. Filipiak-Pittroff B. Krämer U. Hoffmann B. Link E. Beckmann C. et al.Allergies in high-risk schoolchildren after early intervention with cow's milk protein hydrolysates: 10-year results from the German Infant Nutritional Intervention (GINI) study.J Allergy Clin Immunol. 2013; 131: 1565-1573Abstract Full Text Full Text PDF PubMed Scopus (141) Google Scholar No information is apparently available concerning eHF-W. Data reported for pHF-W in an earlier GINI study publication noted peptide sizes of 54% at less than 1500 Da and 18% at greater than 6000 Da.3von Berg A. Koletzko S. Grubl A. Filipiak-Pittroff B. Wichmann H.E. Bauer C.P. et al.The effect of hydrolyzed cow's milk formula for allergy prevention in the first year of life: the German Infant Nutritional Intervention Study, a randomized double-blind trial.J Allergy Clin Immunol. 2003; 111: 533-540Abstract Full Text Full Text PDF PubMed Scopus (391) Google Scholar With the ineffective eHF-W, the comparable reported figures were 84% at less than 1500 Da and 2% at greater than 6000 Da. The US Food and Drug Administration (FDA) recently reviewed information on pHF-W for a qualified health claim for the prevention of atopic dermatitis. In the manufacturer's submission to the FDA, the typical mean molecular weight of peptides in the hydrolysate, across 30 product batches, indicated approximately 2.5% of peptides at greater than 5000 Da.4Nestle Infant Nutrition/Gerber Products company qualified health claim petition for 100% whey-protein partially hydrolysed infant formula and reduced risk of atopic dermatitis. Section C: analytical data regarding the substance. Available at: http://www.regulations.gov/#!documentDetail;D=FDA-2009-Q-0301-0011. Accessed April 2, 2013.Google Scholar Potential differences in methodology between laboratories or changes over time, as well as differing peptide size cutoff points, make such comparisons with studied formulas difficult, and therefore directly comparable data are of particular interest. With the reduction in protein concentrations noted for pHF-W,1von Berg A. Filipiak-Pittroff B. Krämer U. Hoffmann B. Link E. Beckmann C. et al.Allergies in high-risk schoolchildren after early intervention with cow's milk protein hydrolysates: 10-year results from the German Infant Nutritional Intervention (GINI) study.J Allergy Clin Immunol. 2013; 131: 1565-1573Abstract Full Text Full Text PDF PubMed Scopus (141) Google Scholar the new formulation was compared with the previous formulation.5Zeigler E.E. Jeter J.M. Drulis J.M. Nelson S.E. Haschke F. Steenhout P. et al.Formula with reduced content of improved, partially hydrolysed protein and probiotics: infant growth and health.Monatsschr Kinderheilkd. 2003; 151: S65-S71Crossref Scopus (29) Google Scholar The low-protein formulation used a different whey fraction, with less glycomacropeptide and more lactalbumin, than the high-protein formulation. The low-protein pHF-W also contained more small peptides (62.8% at <1000 Da) and fewer large peptides (1.8% at >5000 Da) than the original formulation. Clinical differences between the 2 pHF-W formulas in terms of stool characteristics were hypothesized to be due to differences in the degree of protein hydrolysis.5Zeigler E.E. Jeter J.M. Drulis J.M. Nelson S.E. Haschke F. Steenhout P. et al.Formula with reduced content of improved, partially hydrolysed protein and probiotics: infant growth and health.Monatsschr Kinderheilkd. 2003; 151: S65-S71Crossref Scopus (29) Google Scholar Separate to the protein component, the standard formula and the ineffective eHF-W in the GINI study contained 25% canola oil in the fat blend, whereas no canola oil was present in the effective pHF-W or eHF-C.6GRAS Associates, on behalf of Danone Trading PV. GRAS notification—canola oil use in infant formulas, 6 March 2012. GRAS Notice 000425. Available at: http://www.accessdata.fda.gov/scripts/fcn/gras_notices/GRN000425.pdf. Accessed April 4, 2013.Google Scholar Variations in fat blend can affect fatty acid profiles and might also introduce trace amounts of different proteins,7Poikonen S. Rance F. Puumailanen T.J. Le Manach G. Reunala T. Turjanmaa K. Sensitization and allergy to turnip rape: a comparison between the Finnish and French children with atopic dermatitis.Acta Paediatr. 2009; 98: 310-315Crossref PubMed Scopus (12) Google Scholar with an effect on allergy outcomes difficult to definitively rule out. In summary, the pHF-W and eHF-C used in the GINI study contained a different fat blend than the control formula and the ineffective eHF-W. The pHF-W has since been reformulated using a different whey fraction with a lower protein concentration and apparently a smaller peptide size distribution closer to that of the ineffective eHF-W. There appears to be less data in the public domain for the other studied hydrolyzed protein products. It would be desirable to vary only 1 component between the control and study formulas and to evaluate poststudy formulation changes to ensure efficacy is not affected. Allergies in high-risk schoolchildren after early intervention with cow's milk protein hydrolysates: 10-year results from the German Infant Nutritional Intervention (GINI) studyJournal of Allergy and Clinical ImmunologyVol. 131Issue 6PreviewThe long-term effect of nutritional intervention with hydrolysate infant formulas on allergic manifestations in high-risk children is uncertain. Full-Text PDF ReplyJournal of Allergy and Clinical ImmunologyVol. 132Issue 3PreviewIn his correspondence J. V. Meaney1 expresses concern about the possible effects of the lipid composition of the study formulas used in the German Infant Nutritional Intervention (GINI) study and on poststudy changes in the protein components. We thank Mr Meaney for pointing out these issues and for giving us the chance to clarify. Full-Text PDF