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Two Randomized Trials of the Effect of the Russian Strain of Bacillus Calmette-Guérin Alone or With Oral Polio Vaccine on Neonatal Mortality in Infants Weighing <2000 g in India

Jayaraman, Kumutha, MD*; Adhisivam, Bethou, MB BS, DCH, DNB; Nallasivan, Saravanan, MD, DM; Krishnan, R. Gokul, MD, DM; Kamalarathnam, Chinnathambi, MD, DM; Bharathi, Mangala, MD, DM; McSharry, Brent, MB BS§; Namachivayam, Siva P., MB BS, MEpi¶,‖,**; Shann, Frank, MB BS, DMedSc¶,‖; Boopalan, Sasireka I, MD, DCH; David, Ponrani, RN, RM, BSN; Bhat, B. Vishnu, MB BS, MD

The Pediatric Infectious Disease Journal: February 2019 - Volume 38 - Issue 2 - p 198–202
doi: 10.1097/INF.0000000000002198
Vaccine Reports
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SDC

Background: In randomized trials in Guinea-Bissau, the Danish strain of Bacillus Calmette-Guérin (BCG) reduces neonatal mortality, primarily by reducing deaths from pneumonia and sepsis. Because World Health Organization–prequalified BCG-Denmark was not available in India, we conducted 2 randomized trials to test whether BCG-Russia alone or with oral polio vaccine (OPV) has similar effects to BCG-Denmark.

Methods: We randomized neonates weighing <2000 g to a control group that was not vaccinated before 28 days of age or to receive either BCG-Russia alone (first trial) or BCG-Russia with OPV (second trial) soon after birth. We performed intention-to-treat analysis using Cox hazards models with age as the underlying time and adjusted for weight, sex and inborn versus outborn status.

Results: Administration of BCG-Russia alone had no effect on neonatal mortality (to 28 days of age): 15.6% of 1537 infants died in the BCG-Russia group and 16.1% of 1535 died in the control group; the adjusted hazard ratio was 0.95 [95% confidence interval (CI): 0.80–1.13]. Administration of BCG-Russia with OPV also had no effect on neonatal mortality: 18.0% of 1103 infants died in the BCG-OPV group and 17.6% of 1104 died in the control group; the adjusted hazard ratio was 1.01 (95% CI: 0.83–1.23). The adjusted hazard ratio for the 2 trials combined was 0.98 (95% CI: 0.85–1.11).

Conclusions: BCG-Russia with or without OPV had no effect on neonatal mortality. It is important to determine which strains of BCG have the greatest specific effects (on tuberculosis) and nonspecific effects (on infections other than tuberculosis) in high-mortality regions.

From the *Department of Neonatology, Saveetha Medical College, Chennai, India

Department of Neonatology, Jawaharlal Institute of Postgraduate Medical Education and Research, Pondicherry, India

Department of Neonatology, Institute of Child Health & Hospital for Children, Egmore, Chennai, India

§Paediatric Intensive Care Unit, Starship Children’s Hospital, Auckland, New Zealand

Paediatric Intensive Care Unit, Royal Children’s Hospital, Melbourne, Australia

Department of Paediatrics, University of Melbourne, Melbourne, Australia

**Murdoch Children’s Research Institute, Melbourne, Australia

Department of Neonatology, Institute of Obstetrics & Gynaecology, Egmore, Chennai, India.

Accepted for publication August 6, 2018.

The authors have no funding or conflicts of interest to disclose.

Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal’s website (www.pidj.com).

Address for correspondence: Frank Shann, MB BS, DMedSc, Department of Paediatrics, University of Melbourne, Victoria 3052, Australia. E-mail: shannf@netspace.com.au.

Bacillus Calmette-Guérin (BCG) has both specific effects against tuberculosis and nonspecific (off-target, heterologous) effects against infections other than tuberculosis. Three randomized trials in Guinea-Bissau have found that BCG-Denmark reduces neonatal mortality in infants weighing <2500 g by 38% [95% confidence interval (CI): 17%–54%];1–3 this beneficial nonspecific effect is due mainly to reduced mortality from pneumonia and sepsis.neonatal mortality among infants weighing <2500 g: a randomized controlled trial. Clin Infect Dis. 2017;65:1183–1190.','400');" onMouseOut="javascript:ImageWrapperControl_ImageMouseOut();">3 BCG-Denmark has been shown to upregulate innate immune function by an epigenetic effect mediated by methylation of histone.

4 , 5

However, the only World Health Organization (WHO)–prequalified BCG vaccine licensed in India when these trials began was derived from the Russia-I strain, which may have weaker beneficial nonspecific effects than BCG-Denmark.6 The nonspecific effects of BCG are strongly associated with the presence of a scar,7–10 and BCG-Russia has a lower scar rate than BCG-Denmark.7 , 11 In addition, compared with BCG-Denmark, BCG-Russia is associated with weaker interferon-γ, interleukin-10 and interleukin-12 responses to both specific (mycobacterial) and nonspecific (nonmycobacterial) antigens.11 WHO has recently stressed the importance of obtaining information about the effects of different strains of BCG.12 , 13

The randomized trials in Guinea-Bissau that found that BCG-Denmark reduced neonatal mortality used a combination of BCG-Denmark and oral polio vaccine (OPV),1–3 and a randomized trial in Guinea-Bissau found that when OPV was administered with BCG-Denmark in the first 2 days of life, the mortality hazard ratio was 0.58 (95% CI: 0.38–0.90) compared with BCG without OPV.14

We performed 2 randomized trials in India of the effect on neonatal mortality of BCG-Russia alone and of BCG-Russia with OPV. Neonates weighing <2000 g were studied because these children are not usually vaccinated with BCG until they have gained weight and are discharged from hospital. Neonatal (28 days) mortality was studied because many infants in the control group would be vaccinated with BCG at about 28 days of age and because the beneficial nonspecific effects of BCG last only until a different vaccine is given, usually diphtheria-tetanus-pertussis vaccine at 6 weeks of age.1–3 , 15 , 16

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METHODS

The 2 trials followed the same protocol apart from the vaccines used and the sample sizes, which were adjusted to allow for different predicted mortality rates in the control groups. Infants were eligible for the trial of BCG-Russia alone if they weighed <2000 g and were admitted to the neonatal intensive care unit (NICU) at the Institute of Child Health, Chennai (outborn infants), or the NICU at the adjacent Government Maternity Hospital, Chennai (inborn infants). Infants were eligible for the trial of BCG-Russia with OPV if they weighed <2000 g and were admitted to the NICU at the Jawaharlal Institute of Postgraduate Medical Education and Research in Pondicherry. In both trials, all infants admitted to NICU who weighed <2000 g were enrolled except infants <60 minutes of age; infants unlikely to survive more than 24 hours; infants older than 21 days of age; infants with a major life-threatening malformation; the mother or infant was known to have HIV, hepatitis B, herpes zoster or immunodeficiency; the infant had already received BCG; or the family refused consent. Written informed consent was obtained before randomization.

The first 364 infants enrolled in the trial of BCG-Russia alone were randomized using sealed opaque envelopes; after that, infants were block randomized using a purpose-written computer program that checked eligibility, allocated treatment and recorded the demographic and outcome data. All infants in the trial of BCG-Russia with OPV were block randomized using the purpose-written computer program. In both trials, randomizing blocks were stratified by weight and sex and randomly varied in size from 2–8 participants.

Infants in the intervention group were vaccinated by intradermal injection of BCG-Russia (Serum Institute of India, Pune) as soon as possible after admission to NICU and within 48 hours; a dose of 0.05 mL was used in the trial of BCG-Russia alone and 0.1 mL in the trial of BCG-Russia with OPV. In the trial of BCG with OPV, the first 972 infants in the intervention group received 0.1 mL (2 drops) orally of trivalent OPV (Bharat Immunologicals & Biologicals, Bulandshahr), and the remaining 131 received 0.1 mL (2 drops) orally of bivalent (types 1 and 3) OPV (Bharat Biotech International, Hyderabad). No other vaccines and no therapeutic doses of vitamin A were given to the infants before discharge from hospital. Infants in the control groups were vaccinated with BCG and OPV following standard practice in the nurseries: normally after they had reached at least 2000 g and had been discharged from NICU.

In the trial of BCG-Russia alone, the sample size required was a total of 461 deaths; with a mortality rate of 25% in the control group, 1083 infants were required in each group to have 95% power to detect a 30% reduction in mortality with BCG-Russia with alpha error <0.01. This implied 271 deaths in the control group (1083 × 0.25) and 190 deaths in the BCG-Russia group (1083 × 0.25 × 0.7). In the trial of BCG-Russia with OPV, the sample size required was a total of 385 deaths; with a mortality rate of 19% in the control group, 1213 infants were required in each group to have 95% power to detect a 33.3% reduction in mortality with BCG-OPV with alpha error <0.01. This implied 231 deaths in the control group (1213 × 0.19) and 154 deaths in the BCG-OPV group (1213 × 0.19 × 0.67).

Because a high loss to follow-up was anticipated after discharge from hospital, the planned primary endpoint in both trials was in-hospital death up to 28 days of age with censoring at the time of discharge from hospital, with overall mortality to 28 days of age as a secondary endpoint. Both protocols allowed for the trial to be stopped if the BCG group had a lower mortality than the control group after at least 50% of the planned number of deaths with P < 0.001 (Haybittle-Peto rule) or there were serious side effects from BCG. The trial of BCG-Russia without OPV was approved by the Institutional Ethics Committee of Madras Medical College and registered as CTRI/2018/05/013868. The trial of BCG-Russia with OPV was approved by the Jawaharlal Institute of Postgraduate Medical Education and Research ethics committee and registered as CTRI/2014/03/004450.

In both trials, intention-to-treat statistical analysis was performed using Stata Version 15 (StataCorp, College Station, TX), and the Cox proportional hazard models used age as the underlying time. The proportional hazards assumption of the Cox models were tested using Schoenfeld residuals and separately estimated Kaplan-Meier curves. Tables were constructed using univariable analysis, and the P values for interactions were derived from the logarithms of the risk ratios.17

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RESULTS

BCG-Russia Without OPV

Between October 2013 and October 2015, 3863 infants weighing <2000 g were admitted to the 2 NICUs, but 791 were excluded by the protocol criteria leaving 3072 infants to participate (Fig., Supplemental Digital Content 1a, http://links.lww.com/INF/D293): 1537 were randomized to the BCG-Russia group and 1535 to the control group. The 2 groups were well matched for age, weight, gestational age, sex and proportion inborn (Table 1); compared with infants in the control group, 6.4% more infants in the BCG-Russia group had a mother with a BCG scar, but maternal BCG scar did not affect the BCG-Russia versus control mortality ratio in this trial (Table 2).

TABLE 1

TABLE 1

TABLE 2

TABLE 2

Before they were 28 days of age (usually at about the time of discharge), 49 infants (1.6%) received both OPV and hepatitis B vaccine (17 BCG-Russia, 32 control), and another 30 (1.0%) received OPV alone (15 BCG-Russia, 15 control). We did not censor at the time of these vaccinations as we were performing an intention-to-treat analysis. Apart from BCG-Russia at the time of randomization in the intervention group and OPV alone or with hepatitis B vaccine at about the time of discharge in 79 infants, no other vaccines were given to infants in either group before 28 days of age.

Mortality to 28 days of age was 240 (15.6%) of 1537 infants in the BCG-Russia group and 247 (16.1%) of 1535 infants in the control group (Table 2). By 28 days of age, in the BCG-Russia and control groups, respectively, 234 and 238 infants died in hospital, and 126 and 100 were alive in hospital; among infants discharged before 28 days of age, 1046 and 1087 were known to have survived, 6 and 9 died, and 125 and 101 were lost to follow-up but were deemed likely to survive to 28 days of age by the treating neonatologist. The cause of death in the BCG-Russia and control groups respectively was hyaline membrane disease in 104 and 99, infection in 42 and 43, intra-ventricular hemorrhage in 29 and 12, congenital malformation in 4 and 18, other causes in 66 and 67, and unknown in 2 and 1. There was no statistically significant effect on the BCG-Russia to control mortality ratio of sex, weight, inborn versus outborn or maternal BCG scar (Table 2). Infants died at a median age of 3.0 [interquartile range (IQR), 1.4–6.7] days in the BCG-Russia group and 3.0 (IQR, 1.7–5.2) days in the control group. Surviving infants were discharged at a median age of 6.3 (IQR, 2.9–11.5) days in the BCG-Russia group and 6.1 (IQR, 3.1–11.1) days in the control group. Cox analysis of survival to 28 days of age (without censoring for OPV and hepatitis B vaccine) with age as the underlying time and adjusted for weight, sex and inborn versus outborn status showed no significant effect of BCG-Russia vaccination, with a hazard ratio of 0.95 (95% CI: 0.80–1.13) (Fig., Supplemental Digital Content 2a, http://links.lww.com/INF/D294 and Table, Supplemental Digital Content 3, http://links.lww.com/INF/D295); with censoring at discharge for the 125 BCG-Russia and 101 control infants lost to follow-up (who were all deemed likely to survive to 28 days), the adjusted hazard ratio was almost unchanged at 0.95 (95% CI: 0.80–1.14). There was no significant interaction between sex and death in the first 3 days of life versus death between day 4 and day 28 (Table, Supplemental Digital Content 4, http://links.lww.com/INF/D296). At approximately 3 months of age, 1283 (84%) of 1533 infants in the BCG-Russia group had a scar, and 88 (85%) of 103 infants in the control (late BCG) group had a scar (Table, Supplemental Digital Content 5, http://links.lww.com/INF/D297). There were no serious side effects from BCG-Russia and no cases of disseminated BCG infection.

Because we expected that a high proportion of infants would be lost to follow-up after discharge from hospital, the primary endpoint specified in the protocol was death in hospital up to 28 days of age with censoring at the time of discharge from hospital. Unexpectedly, the wide availability of mobile phones enabled us to contact families and obtain information about survival to 28 days in 90.5% of enrolled infants who had been discharged alive, so neonatal mortality (to 28 days of age) has been used as the main endpoint. However, the results are very similar for the originally specified primary endpoint of in-hospital death up to 28 days of age: 234 (15.2%) of the BCG-Russia group died in hospital versus 238 (15.5%) of the control group. The median time from randomization to death in hospital up to 28 days of age was 2.9 (IQR, 1.4–5.9) days in the BCG-Russia group and 2.8 (IQR, 1.6–4.9) days in the control group. Cox analysis of in-hospital death up to 28 days of age with age as the underlying time and adjusted for weight, sex and inborn versus outborn status gave a hazard ratio of 0.96 (95% CI: 0.80–1.15).

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BCG-Russia With OPV

Between February 2014 and August 2016, 2435 infants <2000 g were admitted to the NICU, but 228 were excluded by the protocol criteria leaving 2207 infants to participate (Fig., Supplemental Digital Content 1b, http://links.lww.com/INF/D293): 1103 were randomized to the BCG-OPV group and 1104 to the control group. The 2 groups were well matched for age, weight, gestational age, sex, the proportion inborn and the proportion who had mothers with a BCG scar (Table 1).

Before they were 28 days of age, 194 (17.6%) of the 1104 control infants were given OPV, but we did not censor at the time of these vaccinations as we were performing an intention-to-treat analysis. In most cases, OPV was given to the control group at about the time of discharge, so censoring for OPV would introduce bias because healthy children being discharged before 28 days of age would be excluded from the analysis from that time on. Apart from BCG-OPV at the time of randomization in the intervention group and OPV at about the time of discharge in 194 controls, no other vaccines were given to infants in either group before 28 days of age.

Mortality to 28 days of age was 198 (18.0%) of 1103 infants in the BCG-OPV group and 194 (17.6%) of 1104 in the control group (Table 2). By 28 days of age, in the BCG-OPV and control groups respectively: 182 and 185 infants died in hospital, and 74 and 76 were alive in hospital; among infants discharged before 28 days of age, 809 and 804 were known to have survived, 14 and 9 died, and 24 and 30 were lost to follow-up (all were deemed by the neonatologist as likely to survive, except for 2 of the 24 in the BCG-OPV group who were considered likely to die before 28 days of age). These 2 infants weighed 870 g and 1330 g; both had hyaline membrane disease and were mechanically ventilated and on intravenous fluids, inotropes and antibiotics up to the time they left hospital against medical advice at 5 and 4 days of age. The cause of death in the BCG-OPV and control groups respectively was infection in 148 and 112, hyaline membrane disease in 19 and 47, necrotizing enterocolitis in 8 and 5, other causes in 18 and 31, and unknown in 1 and 1. There was no statistically significant effect on the BCG-OPV to control mortality ratio of sex, weight, inborn versus outborn or maternal BCG scar (Table 2). Infants died at a median age of 3.9 (IQR, 2.6–5.8) days in the BCG-OPV group and at 4.0 (IQR, 2.6–7.5) days in the control group. Surviving infants were discharged at a median age of 8.0 (IQR, 5.3–13.7) days in the BCG-OPV group and 8.4 (IQR, 5.3–13.2) days in the control group. Cox analysis of survival to 28 days of age (without censoring for OPV in controls) with age as the underlying time and adjusted for weight, sex and inborn versus outborn status showed no significant effect of BCG-OPV vaccination, with a hazard ratio of 1.01 (95% CI: 0.83–1.23) (Fig., Supplemental Digital Content 2b, http://links.lww.com/INF/D294 and Table, Supplemental Digital Content 3, http://links.lww.com/INF/D295); with censoring at discharge for the 24 BCG-OPV and 30 control infants lost to follow-up, the adjusted hazard ratio was unchanged at 1.01 (95% CI: 0.83–1.23). There was no significant interaction between sex and death in the first 3 days of life versus death between day 4 and day 28 (Table, Supplemental Digital Content 4, http://links.lww.com/INF/D296). At approximately 3 months of age, 717 (86%) of 834 infants in the BCG-OPV group had a scar, and 700 (84%) of 830 infants in the control (late BCG) group had a scar (Table, Supplemental Digital Content 5, http://links.lww.com/INF/D297). There were no serious side effects from BCG-Russia or OPV and no cases of disseminated BCG infection.

As with the trial of BCG-Russia alone, mobile phone contact enabled us to obtain information about survival to 28 days in a high proportion (96.8%) of enrolled infants who had been discharged alive, so neonatal mortality (to 28 days of age) has been used as the main endpoint in the analysis. However, the results are very similar for the originally specified primary endpoint of in-hospital death up to 28 days of age: 182 (16.5%) of the BCG-OPV group died in hospital versus 185 (16.8%) of the control group. The median time from randomization to death in hospital up to 28 days of age was 3.8 (IQR, 2.6–5.7) days in the BCG-OPV group and 4.0 (IQR, 2.6–7.2) days in the control group. Cox analysis of in-hospital death up to 28 days of age with age as the underlying time and adjusted for weight, sex and inborn versus outborn status gave a hazard ratio of 0.97 (95% CI: 0.79–1.19).

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DISCUSSION

These 2 large randomized trials did not detect any effect of BCG-Russia on neonatal mortality in infants weighing <2000 g who were admitted to neonatal intensive care: the adjusted hazard ratio for neonatal mortality (up to 28 days of age) was 0.95 (95% CI: 0.79–1.13) with BCG-Russia alone and 1.01 (95% CI: 0.83–1.23) with BCG-Russia plus OPV; the adjusted hazard ratio for the 2 trials combined was 0.98 (95% CI: 0.85–1.11) with both fixed and random effects models. The trials were not blinded, but this is unlikely to have influenced the outcome: the research assistant supervising each of the trials had no role in the management of the infants, and the endpoint of mortality did not involve subjective judgement.

In a randomized trial in Guinea-Bissau, OPV plus BCG-Denmark in the first 2 days of life had a mortality hazard ratio of 0.58 (95% CI: 0.38–0.90) compared with BCG-Denmark alone.14 In contrast, the addition of OPV had no effect in our trial when it was given with BCG-Russia. The apparent contradiction may be explained by the fact that BCG-Denmark reduces neonatal mortality in Guinea-Bissau, whereas BCG-Russia has no effect on neonatal mortality in India. The nonspecific effects of vaccines are profoundly influenced by whether they are given alone or with other vaccines (as shown in Figure 5 of the WHO review of nonspecific effects),15 which suggests that the nonspecific effects of OPV may be reduced or absent if it is given with a poorly active rather than highly active strain of BCG.

A systematic review of randomized trials of BCG found no evidence that its specific effect against tuberculosis was associated with BCG strain;18 however, this was an ecologic analysis prone to confounding, only 2 of the 18 trials reported comparisons by strain (Phipps-Pasteur, Denmark-Pasteur) and neither was in neonates, and none of the trials studied BCG-Russia or BCG-Japan. Evidence for differences between strains in their specific effect on tuberculosis comes from a randomized trial in 303,092 neonates in Hong Kong where the incidence of tuberculosis after BCG-Glaxo was 1.8 (95% CI: 1.3–2.5) times higher than after BCG-Pasteur,6 , 19 and from a cohort study in Kazakhstan where the incidence of tuberculosis after vaccination of neonates with BCG-Russia was 2.5 (95% CI: 2.0–3.1) times higher than after BCG-Japan.20 In addition, in a randomized trial in Australia, the proportion of mycobacterium-specific polyfunctional CD4 T cells was significantly lower in infants immunized with BCG-Russia rather than BCG-Denmark or BCG-Japan.21

The beneficial nonspecific effects of BCG (but not the specific effects) are strongly associated with the presence of a scar,7–10 and BCG-Russia has a lower scar rate than BCG-Denmark.7 , 11 In a cohort study in Uganda, only 52% of 1124 infants developed a scar after vaccination with BCG-Russia compared with 93% of 169 infants vaccinated with BCG-Denmark, and BCG-Russia was associated with lower interferon-γ, interleukin-10 and interleukin-12 responses to both specific (mycobacterial) and nonspecific (nonmycobacterial) antigens.11 In a cohort study of 15,911 children vaccinated with BCG-Russia in rural Guinea-Bissau, only 52% developed a scar (the same proportion as in Uganda), and children with a scar had 26% (95% CI: 4%–44%) lower all-cause mortality and 80% (95% CI: 45%–93%) lower mortality from respiratory infections.7

Three randomized trials in Guinea-Bissau have found that BCG-Denmark reduces neonatal (28 days) mortality by 38% (95% CI: 17%–54%),1–3 so the lack of effect of BCG-Russia in our trials in India is further evidence that BCG-Russia may have less potent nonspecific effects than BCG-Denmark. Other possible explanations for the lack of nonspecific effects of BCG-Russia in our trials are that BCG does not influence neonatal mortality or that there are regional differences between India and West Africa. The latter explanation is unlikely: 2 of the studies in the WHO-sponsored review of the nonspecific effects of vaccines were cohort studies of BCG in India,15 and both suggested that BCG probably does have nonspecific effects in India.22 , 23 The study in Tamil Nadu reported a relative risk of 0.44 (95% CI: 0.29–0.66) for BCG versus no BCG,22 and the study in Pune reported a relative risk of 0.60 (95% CI: 0.18–1.97);23 unfortunately, the authors of these articles have no record of the strains of BCG used.

It is not known whether BCG strains that have stronger specific effects always have stronger nonspecific effects, but the combined evidence from our 2 randomized trials of BCG-Russia in neonates in India, randomized trials and observational studies in Guinea-Bissau,1–3 , 6 , 7 a randomized trial in Australia21 and observational studies in Kazakhstan20 and Uganda11 suggest that BCG-Denmark and BCG-Japan may provide greater protection than BCG-Russia against both tuberculous and nontuberculous infections. In 2014, the United Nations Children's Fund (UNICEF) supplied 78 million doses of BCG-Russia (from Serum Institute of India, Pune, and Bul Bio, Bulgaria), 32 million doses of BCG-Japan, and 10 million doses of BCG-Denmark,24 so most infants in low-income countries are vaccinated with BCG-Russia, and only a minority receive BCG-Denmark or BCG-Japan. This suggests that greatly improved protection against both tuberculosis and all-cause mortality might be achieved by performing randomized trials that compare different strains of BCG and their specific and nonspecific effects and then standardizing production on the most effective genotypes in those strains. This might achieve further large reductions in child mortality at very little extra cost.

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ACKNOWLEDGEMENTS

For their invaluable assistance, the authors thank Dr. V Namachivayam (Cuddalore) and Ms. A Naveena (Chennai) and also the medical and nursing staff of the Departments of Neonatology at the Jawaharlal Institute of Postgraduate Medical Education and Research in Pondicherry, the Institute of Child Health and the Hospital for Children in Chennai, and the Institute of Obstetrics and Gynaecology in Chennai.

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Keywords:

Bacille Calmette-Guérin; oral polio vaccine; neonatal mortality; heterologous immunity; randomized trial

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