Journal of Infectious Diseases – Volume 211 Issue 3 February 1, 2015

Journal of Infectious Diseases
Volume 211 Issue 3 February 1, 2015
http://jid.oxfordjournals.org/content/current

EDITORIAL COMMENTARY
Delayed BCG Vaccination—Time to Take a Shot
Alexander W. Kay1 and Catherine A. Blish2,3
Author Affiliations
1Department of Pediatrics
2Department of Medicine
3Stanford Immunology, Stanford University School of Medicine, California
(See the major article by Toukam Tchakoute et al on pages 338–46.)
[Excerpt]
The BCG vaccine is often derided for the lack of efficacy in preventing Mycobacterium tuberculosis infection and pulmonary disease in adults. However, BCG vaccine remains a highly effective and cost-efficient intervention to prevent tuberculous meningitis and miliary tuberculosis in infants, reducing the incidence of these life-threatening and debilitating infections by approximately 75% [1, 2]. In addition, BCG vaccine coverage rates typically exceed those of other vaccines because it can be administered at birth as a single vaccination [3].

However, this strength of the BCG vaccination strategy has become a liability because of the risks of administering BCG vaccine to human immunodeficiency virus (HIV)–infected infants. The HIV diagnosis is typically not made until the second or third month of life in resource-limited settings, and BCG vaccination in this population results in unacceptably high rates of disseminated BCG disease of 417–992 cases per 100,000 vaccinations, with a mortality of approximately 75% [4–6]. To put this in perspective, this rate of disseminated BCG disease exceeds the rate of disseminated disease due to M. tuberculosis in the same South African population of HIV-infected infants, which is estimated to be 241 cases per 100,000 [7]. In light of this significant risk for the vaccine to cause harm, the World Health Organization (WHO) now identifies known HIV infection in infants, or HIV exposure and symptoms concerning for HIV, as contraindications to BCG vaccination [8, 9]. The rationale for this recommendation is augmented by the unknown clinical efficacy of BCG vaccination in HIV-infected infants and the immunologic data suggesting that BCG given at birth is unlikely to be efficacious in this population [10]….

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Delaying BCG Vaccination Until 8 Weeks of Age Results in Robust BCG-Specific T-Cell Responses in HIV-Exposed Infants
Christophe Toukam Tchakoute1, Anneke C. Hesseling4, Elvis B. Kidzeru1, Hoyam amieldien1,2,
Jo-Ann S. Passmore2,5, Christine E. Jones3,6, Clive M. Gray1,5, Donald L. Sodora7 and Heather B. Jaspan1,7
Author Affiliations
1Division of Immunology
2Division of Medical Virology
3Institute of Infectious Disease and Molecular Medicine, Department of Clinical Laboratory Sciences, University of Cape Town
4Desmond Tutu TB Centre, Department of Paediatrics and Child Health, Faculty of Medicine and Health Sciences, Stellenbosch University, Cape Town
5National Health Laboratory Services, South Africa
6Paediatric Infectious Diseases Research Group, St George’s, University of London, United Kingdom
7Seattle Biomedical Research Institute, Washington
Presented in part: 6th South African AIDS Conference, Durban, South Africa, June 2013; World Society for Pediatric Infectious Diseases Conference, Cape Town, South Africa, November 2013.
Abstract
Background
BCG vaccination prevents disseminated tuberculosis in children, but it is contraindicated for persons with human immunodeficiency virus (HIV) infection because it can result in severe disease in this population. In tuberculosis-endemic regions, BCG vaccine is administered soon after birth, before in utero and peripartum HIV infection is excluded. We therefore assessed the immunogenicity of BCG vaccine in HIV-exposed infants who received BCG at birth or at 8 weeks of age.
Methods
HIV-exposed, uninfected infants were randomly assigned to receive BCG vaccination at birth (the early vaccination arm) or 8 weeks of age (the delayed vaccination arm). BCG-specific proliferative and intracellular cytokine responses were assessed in 28 infants per arm at 6, 8, and 14 weeks of life.
Results
There was no difference in BCG-specific T-cell proliferation between the study arms 6 weeks after vaccination. However, at 14 weeks of age, the frequency of interferon γ–expressing CD4+ T cells and multifunctional BCG-specific responses in the delayed vaccinated arm were significantly higher than those in the early vaccination arm (P = .021 and P = .011, respectively).
Conclusions
The immunogenicity of BCG vaccination in HIV-exposed, uninfected infants is not compromised when delayed until 8 weeks of age and results in robust BCG-specific T-cell responses at 14 weeks of age. These findings support further evaluation of this modified BCG vaccination strategy for HIV-exposed infants.
Clinical Trials Registration. NCT02062580.

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Live Attenuated and Inactivated Influenza Vaccines in Children
Natalia A. Ilyushina1,a, Brenda C. Haynes1, Anne G. Hoen2,b, Alexey M. Khalenkov1,b, Molly L. Housman3, Eric P. Brown4, Margaret E. Ackerman4, John J. Treanor5, Catherine J. Luke6, Kanta Subbarao6 and Peter F. Wright1
Author Affiliations
1Department of Pediatrics
2Department of Community and Family Medicine
3Department of Microbiology and Immunology, Geisel School of Medicine at Dartmouth
4Department of Thayer School of Engineering at Dartmouth, Hanover, New Hampshire
5Department of Medicine, University of Rochester Medical Center, New York
6Laboratory of Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland
Presented in part: American Society for Virology, 31st Annual Meeting, Madison, Wisconsin 21–25 July 2012; Pediatric Academic Societies, Boston, Massachuetts, 28 April–1 May, 2012.
a Present affiliation: Food and Drug Administration Center for Drug Evaluation and Research, Bethesda, Maryland.
b A. G. H. and A. M. K. contributed equally to this work.
Abstract
Background
Live attenuated influenza vaccine (LAIV) and inactivated influenza vaccine (IIV) are available for children. Local and systemic immunity induced by LAIV followed a month later by LAIV and IIV followed by LAIV were investigated with virus recovery after LAIV doses as surrogates for protection against influenza on natural exposure.
Methods.
Fifteen children received IIV followed by LAIV, 13 an initial dose of LAIV, and 11 a second dose of LAIV. The studies were done during autumn 2009 and autumn 2010 with the same seasonal vaccine (A/California/07/09 [H1N1], A/Perth/16/09 [H3N2], B/Brisbane/60/08).
Results.
Twenty-eight of 39 possible influenza viral strains were recovered after the initial dose of LAIV. When LAIV followed IIV, 21 of 45 viral strains were identified. When compared to primary LAIV infection, the decreased frequency of shedding with the IIV-LAIV schedule was significant (P = .023). With LAIV-LAIV, the fewest viral strains were recovered (3/33)—numbers significantly lower (P < .001) than shedding after initial LAIV and after IIV-LAIV (P < .001). Serum hemagglutination inhibition antibody responses were more frequent after IIV than LAIV (P = .02). In contrast, more mucosal immunoglobulin A responses were seen with LAIV.
Conclusions.
LAIV priming induces greater inhibition of virus recovery on LAIV challenge than IIV priming. The correlate(s) of protection are the subject of ongoing analysis.
Clinical Trials Registration. NCT01246999.