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DELAYED BCG VACCINATION -- TIME TO TAKE A SHOT

Sunday, 11th of January 2015 Print

DELAYED BCG VACCINATION—TIME TO TAKE A SHOT

  1. Alexander W. Kay1 and
  2. Catherine A. Blish2,3

+ Author Affiliations

1.      1Department of Pediatrics
2.      2Department of Medicine
3.      3Stanford Immunology, Stanford University School of Medicine, California
  1. Correspondence: Catherine A. Blish, MD, PhD, Division of Infectious Disease and Geographic Medicine, Department of Medicine, 300 Pasteur Dr, Lane Bldg, L134, Stanford, CA 94305-5107 (cblish@stanford.edu).

Also at http://jid.oxfordjournals.org/content/211/3/335.full with weblinks

See the major article by Toukam Tchakoute et al on pages 338–46, accessible at

 http://jid.oxfordjournals.org/content/211/3/338.full

 

 

 

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% [46]. 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].

Notably, there have been significant advances in pediatric HIV care, such as more-timely infant diagnostic tests and universal antiretroviral therapy for all infected infants, since many of the prevalence estimates of disseminated BCG disease were calculated. It is unknown how these changes in care affect the risk of disseminated BCG disease in HIV-infected infants, but there are data suggesting that early initiation of antiretroviral therapy reduces the incidence of BCG immune reconstitution adenitis [11]. Novel vaccination strategies and ongoing estimates of BCG disease in HIV-infected infants are needed, because the rate of tuberculosis exposure and disease in this population remains exceedingly high [7, 12, 13] and because other interventions, such as preexposure isoniazid prophylaxis, have not proven to be successful in preventing tuberculosis in HIV-infected infants [14].

At the same time, advances in preventing maternal-to-child transmission of HIV have significantly reduced the rates of infant infection and, thus, the risk for severe complications following BCG vaccine administration in many countries throughout sub-Saharan Africa over the last several years [15, 16]. These successes have simultaneously increased the population of HIV-exposed but uninfected (HEU) infants, raising very important questions about the risks and benefits of BCG vaccination in HIV-exposed infants. The WHO provides more-nuanced recommendations for this population of exposed infants. Current WHO tuberculosis treatment guidelines cite the coverage and success of local prevention of maternal-to-child transmission programs, the possibility of deferring BCG vaccination based on the timeliness of appropriate HIV diagnostic tests, and the provision of early antiretroviral therapy as factors that influence the risk-benefit ratio of BCG vaccination in HIV-exposed infants [9]. These factors focus on mitigating the risk of inadvertently giving BCG vaccination to HIV-infected infants; however, of equal importance are the unknowns surrounding the immunogenicity and clinical efficacy of this vaccine in HIV-exposed infants.

HEU infants are immunologically distinct from unexposed infants [1719] and experience higher rates of clinically severe infections and infant mortality [2022]. There are conflicting data on vaccine-induced immunity in this population, although humoral responses seem to be relatively preserved [23, 24]. Data regarding cellular immune responses to BCG vaccination have been less encouraging, with decreased BCG-specific interferon γ (IFN-γ) production [25, 26] and T-cell polyfunctionality [27] after vaccination in HEU infants. Although the immune correlates of protection from tuberculosis are unknown, potent cytokine-secreting T cells are critical for immunity to tuberculosis [28, 29]. Therefore, these findings suggest that BCG vaccine may be less effective in this population when administered at birth. Certainly, these data provide the incentive to attempt delayed vaccination strategies in HIV-exposed infants, both to enhance BCG immunogenicity and to prevent inadvertent BCG vaccination of HIV-infected infants.

In this issue of The Journal of Infectious Diseases, Tchakoute et al address this very important question, determining whether administering the BCG vaccine at 8 weeks of age instead of birth alters BCG-specific T-cell responses in a South African population with high rates of HIV infection and tuberculosis. From a larger randomized trial of 149 HIV-exposed infants assigned to undergo vaccination at birth or at 8 weeks of age, 28 infants per arm were randomly selected for intensive study of BGG-specific T-cell responses. The authors found no evidence that delayed vaccination compromised immune responses. At 6 weeks following vaccination, there were no major differences in T-cell proliferative responses to BCG between infants vaccinated at birth and those vaccinated at 8 weeks of age. In fact, BCG-specific CD4+ T cell IFN-γ production and T-cell polyfunctionality were higher at 14 weeks of life in the delayed vaccination group, compared with those vaccinated at birth. Thus, delayed vaccination was not inferior and, in fact, could even enhance immunity because tuberculosis exposures tend to increase during infancy, potentially making the 14-week time point a more relevant measure.

These data are particularly interesting when viewed in the context of the existing, although conflicting, data from South Africa and Gambia on delayed BCG vaccination in HIV-unexposed infants [30, 31]. Kagina et al previously demonstrated that HIV-unexposed infants in South Africa administered BCG vaccine at 10 weeks of age had higher frequencies of BCG-specific, polyfunctional CD4+ T cells at 1 year of age, compared with infants vaccinated at birth. In contrast, Burl et al evaluated BCG-specific cytokine responses from peripheral blood mononuclear cell (PBMC) cultures 18 weeks following BCG vaccination at birth vs 18 weeks of age and found decreased IFN-γ and interleukin 17 production in the delayed vaccination group but no differences in responses when both groups were evaluated at 36 weeks of age. Interestingly, in this study, the authors attributed prevaccination responses to purified protein derivative antigens in the delayed vaccination group to interval exposure to environmental nontuberculous mycobacteria (NTM).

Such environmental exposures to NTM prior to BCG vaccination are thought to reduce the immune response to the vaccine, possibly explaining the increased efficacy of BCG vaccine in locations further from the equator, where NTM species are less abundant, and in newborns with limited environmental exposures [2, 32]. Ultimately, these conflicting data suggest the need for studies in multiple geographic locations. It is also unclear whether the increased interval of 18 weeks in the Gambian study, compared with 8 and 10 weeks in the South African studies, contributed to increased environmental NTM exposure. While the difference of 8 weeks seems relatively small, it may be significant in light of the dramatic changes in oral-motor capabilities that occur in infants during that interval.

Tchakoute et al have established that BCG vaccination induces equal or enhanced T-helper type 1 cytokine responses in HIV-exposed infants when delayed until 8 weeks of age. This strongly suggests that this strategy should be explored further as a safer alternative to vaccination at birth. An important consideration is that all studies to date have measured immunologic responses, and although it is generally assumed that more-potent BCG-specific T-cell responses are markers of a more successful immune response to BCG vaccination, it is unknown what threshold is clinically significant. Undeniably, these data need to be correlated with clinical outcomes, despite the challenges in evaluating clinical end points for tuberculosis in infants [33] and the large cohort that would be required to explore differences in outcomes such as tuberculous meningitis and miliary tuberculosis.

Another important consideration raised by Tchakoute et al is that clinical efficacy is not the only measure of a change in immunization schedule. BCG vaccine is among the worlds most widely used vaccines and typically has the highest vaccine coverage among those included in the expanded program on immunization [34]. While there have been improvements in retention in vaccine programs, drop out rates remain unacceptably high throughout much of sub-Saharan Africa [35]. A decrease in coverage of only a few percentage points could have a significant impact on tuberculosis-related mortality for HIV-exposed infants. In addition, although Tchakoute et al suggest that tuberculosis exposure in infants <2 months of age is uncommon, this may not necessarily be true in HIV-exposed infants living in areas of high tuberculosis prevalence. A study of HIV-exposed infants in South Africa confirmed tuberculosis source case exposures in 10.1% of 3–4-month-old infants [12]. In Kenya, 10.9% of 6-month-old HIV-exposed infants were found to have positive T-spot IFN-γ release assays [13]. Therefore, the risk of tuberculosis exposure prior to delayed BCG vaccination may not be trivial.

Despite the risks, this work by Tchakoute et al furthers the argument for rigorous clinical studies designed to evaluate the impact of delayed BCG vaccination in HEU infants. The possibility of improving the efficacy and safety of this important vaccine for all HIV-exposed infants should be investigated to the fullest extent.

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Notes

Financial support. This work was supported by the National Institutes of Health (Directors New Innovator Award DP2 AI11219301 to C. A. B.).

Potential conflict of interest. Both authors: No reported conflicts.

Both authors have submitted the ICMJE form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed.

  • Received July 29, 2014.
  • Accepted July 29, 2014.
  • © The Author 2014. Published by Oxford University Press on behalf of the Infectious Diseases Society of America. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com

 

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Editors choice: Delaying BCG Vaccination Until 8 Weeks of Age Results in Robust BCG-Specific T-Cell Responses in HIV-Exposed Infants J Infect Dis. (2015) 211 (3): 338-346 first published online August 8, 2014 doi:10.1093/infdis/jiu434

 

 

 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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