Abstract
Background: The use of different limbs for the administration of sequential doses of an intradermal rabies vaccine was shown to result in reduced vaccine immunogenicity. We aimed to assess whether this phenomenon also occurs with routine infant vaccines. Methods: In this open-label, randomised, controlled study, eligible healthy infants 6-12 weeks of age recruited through five clinical trials units (four in the UK and one in Malta) were randomly assigned in a 1:1 ratio to two vaccination groups: consistent limb or alternating limb. Infants in the consistent limb group received the diphtheria-tetanus-acellular pertussis-inactived polio-. Haemophilus influenzae type b combined vaccine (DTaP-IPV-Hib) at 2, 3, and 4 months of age, and the pneumococcal conjugate vaccine (PCV13) at 2, 4, and 12 months, all administered to the right leg. Infants in the alternating limb group received DTaP-IPV-Hib in the left leg at 2 months and in the right leg at 3 and 4 months; and PCV13 in the left leg at 2 months, in the right leg at 4 months, and in the left arm at 12 months. All infants in both groups received the combined H influenzae type b and capsular group C Neisseria meningitidis tetanus toxoid conjugate vaccine (Hib-MenC-TT), administered in the left leg at 12 months. Randomisation was achieved by randomly generated codes, with permuted block size of 30, and was stratified by study site. Group allocation was not masked from study staff and parents of participants after enrolment, but group allocation was masked from laboratory staff assessing blood samples. The current study was a prespecified secondary objective of a parent phase 4 trial that assessed the induction of immunity following varying schedules of vaccination with glyco-conjugate capsular group C Neisseria meningitidis (Men C) vaccines in infancy. The objective of the current study was to compare the immunogenicity and reactogenicity of vaccines delivered in either consistent or alternating limbs. Immunogenicity was assessed by comparing serum IgG geometric mean concentrations at 5, 12, 13, and 24 months, analysed per protocol. This study is registered with ClinicalTrials.gov, number NCT01129518. Findings: Between July 5, 2010, and Aug 1, 2013, we enrolled 509 infants and randomly allocated them to the consistent limb group (n=254) or the alternating limb group (n=255). Anti-. H influenzae type b anti-polyribosylribitol phosphate IgG geometric mean concentrations were lower in the consistent limb group than in the alternating limb group at 5 months (consistent limb 0·41 μg/mL [95% CI 0·31-0·54] vs alternating limb 0·61 μg/mL [0·45-0·82]; p=0·0268) and at 12 months (0·35 μg/mL [0·28-0·43] vs 0·50 μg/mL [0·40-0·62]; p=0·0136). Anti-tetanus toxoid antibody IgG geometric mean concentrations were lower in the consistent limb group (1·63 IU/mL [95% CI 1·40-1·90]) than in the alternating limb group (2·30 IU/mL [1·97-2·68]) at 13 months (p=0·0008) and at 24 months (0·44 IU/mL [0·37-0·52] vs 0·61 IU/mL [0·51-0·73]; p=0·0074). Anti-pneumococcal IgG geometric mean concentrations were similar between both groups at all timepoints. The proportions of participants who had adverse events did not differ between the two groups. Interpretation: Use of different (alternating) limbs for sequential doses of routine infant vaccines does not reduce, and might enhance, immunogenicity. The underlying mechanism for this finding warrants further research. Funding: NIHR Oxford Biomedical Research Centre and GlaxoSmithKline Biologicals.
| Original language | English |
|---|---|
| Pages (from-to) | 172-180 |
| Number of pages | 9 |
| Journal | The Lancet Infectious Diseases |
| Volume | 15 |
| Issue number | 2 |
| DOIs | |
| Publication status | Published - 1 Feb 2015 |
Bibliographical note
Funding Information:MAI has received travel grants from GlaxoSmithKline for attendance at conferences. AKh has received financial support from GlaxoSmithKline Biologicals and Novartis Vaccines and Diagnostics to attend scientific meetings. DP has received travel grants from GlaxoSmithKline to attend scientific meetings. JM has received grants from NIHR Oxford Biomedical Research Centre UK, GlaxoSmithKline Biologicals, and the Belgium and European Society of Paediatric Infectious Diseases. AKe has received travel grants from vaccine manufacturers for attendance at conferences. XB has received grants from Perform contract research on behalf of Public Health England for Baxter Biosciences, GSK, Pfizer, Novartis, Sanofi Pasteur, and Sanofi Pasteur MSD. HF undertakes contract research on behalf of Public Health England for Baxter Biosciences, GSK, Pfizer, Novartis, Sanofi Pasteur, and Sanofi Pasteur MSD. MDS has received grants and non-financial support from GlaxoSmithKline; grants and other salary support from NIHR Oxford Biomedical Research Centre; and non-financial support from GlaxoSmithKline, Novartis Vaccines, Pfizer, and Baxter. PTH has received grants from GSK, Pfizer, Novartis, and SPSMD. AF has received grants from GSK, AstraZeneca, Alios, Pfizer, Novartis, and SPSMD, and consultancy fees and honoraria, paid to his employers, from the same companies as well as Takeda. He is a member of the WHO European Technical Advisory Group of Experts on Immunisation and the UK Departments of Health's Joint Committee on Vaccination and Immunisation. RB has received grants from Perform contract research on behalf of Public Health England for Baxter Biosciences, GSK, Pfizer, Novartis, Sanofi Pasteur, and Sanofi Pasteur MSD. SNF reports part funding for this project from GSK, via the NIHR Oxford BRC; personal fees from Novartis, Pfizer, and Sanofi; and grants from Pfizer, Sanofi, GSK, Novartis, and Cubist. AJP has received grants from the NIHR Oxford Biomedical Research Centre and GSK Vaccines to fund this research; has previously received grants from Pfizer vaccines, Novartis vaccines, and GSK vaccines; and is the Chair of the UK Departments of Health's Joint Committee on Vaccination and Immunisation. The views expressed in this report do not necessarily represent those of the Department of Health or the Joint Committee on Vaccination and Immunisation (of which AJP is the chair). ASJM, MV, DC, SA-M, CW, ES, RA, and EM declare no competing interests.
Funding Information:
This was an investigator-initiated study and was sponsored by the University of Oxford. GlaxoSmithKline Biologicals reviewed the protocol and commented on the report but the investigators retained editorial control. The funders of the study had no role in the study design, data collection and analysis, data interpretation, preparation of the report, or the decision to submit for publication. Laboratory analysis was done at the Vaccine Evaluation Unit, Public Health England (formerly the Health Protection Agency). AJP acts as a guarantor of the study. The corresponding author had full access to all the data in the study and had final responsibility for the decision to submit for publication.
Funding Information:
AJP and MDS are Jenner Investigators. We acknowledge the contributions of all who were involved in this study and thank all participants and their families. We also acknowledge the support of the National Institute for Health Research Clinical Research Network.
Publisher Copyright:
© 2015 Elsevier Ltd.
Copyright:
Copyright 2015 Elsevier B.V., All rights reserved.
