Thursday, 29th of January 2015 |
Received 12 May 2014, Revised 11 July 2014, Accepted 27 August 2014, Available online 16 September 2014
Full text, with figures, is at http://www.sciencedirect.com/science/article/pii/S0264410X14012201
•Newborns were randomised to OPV at birth (OPV0) together with BCG vs BCG alone.
•In vitro cytokine responses to PPD and BCG were reduced in the OPV + BCG group.
•Innate responses, cell distribution or inflammation markers were not affected.
•The first randomised trial showing heterologous immunological effects of OPV0.
Vaccines may have non-specific effects. An observational study from Guinea-Bissau suggested that oral polio vaccine at birth (OPV0) provided with Bacillus Calmette–Guérin (BCG) vaccine was associated with down-regulation of the immune response to BCG vaccine 6 weeks later. Based on the previous finding, we wanted to test our a priori hypothesis that OPV would dampen the immune response to BCG, and secondarily to test immune responses to other antigens.
The study was conducted at the Bandim Health Project in Guinea-Bissau in 2009–2010. Infants were randomised to OPV0 + BCG versus BCG alone at birth, and subsequently randomised to have a blood sample taken at 2, 4 or 6 weeks post-randomisation. Excreted levels of cytokines (IL-2, IL-5, IL-10, TNF-α and IFN-γ) were measured from whole blood in vitro stimulations with a panel of recall vaccine antigens (BCG, PPD, OPV), mitogen (PHA) or innate agonists (LPS, Pam3cys, PolyI:C). Additionally, we measured the local reaction to BCG, white blood cell distribution, C-reactive protein (CRP) and retinol-binding protein (RBP). Cytokine production was analysed as the prevalence ratios of responders above the median.
Blood samples from 430 infants (209 OPV0 + BCG; 221 BCG alone) were analysed. There were no strong differences in effects 2, 4 and 6 weeks post-randomisation and subsequent analyses were performed on the pooled data. As hypothesised, receiving OPV0 + BCG versus BCG alone was associated with significantly lower prevalence of IFN-γ responses to PPD (prevalence ratio (PR): 0.84 (0.72–0.98)) and reduced IL-5 to PPD (PR: 0.78 (0.64–0.96)). No effects were observed for CPR, RBP, white blood cell distribution, or BCG scar prevalence.
The results corroborate that OPV attenuates the immune response to co-administered BCG at birth.
According to current vaccination policy, infants in high-risk countries should receive oral polio vaccine at birth (OPV0) followed by three doses in infancy [1]. The first dose at birth is usually given together with Bacillus Calmette-Guérin vaccine (BCG) against tuberculosis (TB). Recently, OPV was temporarily missing in Guinea-Bissau. In this “natural experiment”, not receiving OPV0 was associated with increased infant male survival but a weak tendency for increased mortality among females, indicating that OPV0 may have a sex-differential effect on infant mortality [2]. The BCG given at birth is known to induce a potent pro-inflammatory Th1-polarising IFN-γ response to purified protein derivate from Mycobacterium tuberculosis (PPD) [3]. However, in the “natural experiment” receiving OPV0 with BCG at birth was associated with significantly lower IFN-γ in response to PPD at 6 weeks of age, and a moderately lower likelihood of developing a BCG scar, suggesting that OPV0 may dampen the response to BCG [4]. It could be speculated that part of the lower BCG vaccine efficacy in low-income countries [5] might be due to simultaneous OPV0.
To further investigate the heterologous effects of OPV, we carried out a large randomised-controlled trial (RCT) testing the effects of providing OPV with BCG at birth on overall survival (Lund, submitted). The present sub-study aimed at investigating the immunological effects of OPV together with BCG at birth on the developing immune response at 2, 4 and 6 weeks of age, including innate and non-polio specific adaptive responses, non-specific inflammation markers and immune cell distribution. Our a priori hypothesis was that OPV would dampen the IFN-γ response to PPD.
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