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 &lt;2000 g in India

Kumutha, J.; Adhisivam, B; Nallasivan, Saravanan; Krishnan, R Gokul; Kamalarathnam, Chinnathambi; Bharathi, M.; McSharry, Brian P.; Namachivayam, Siva P.; Shann, Frank; Boopalan, Sasireka I; David, Ponrani; Bhat, B. Vishnu

doi:10.1097/inf.0000000000002198

Cited by 50 publications

(54 citation statements)

References 81 publications

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“…Most trends noted in the development of the concept of the NSEs of MV starting from 1979 turned out to be consistent in later studies. Several RCTs of MV, BCG and OPV have found strong beneficial NSEs (41,55,63), though the results have not been universally consistent (44,79).…”

Section: Implications and Conclusionmentioning

confidence: 99%

“…BCG strongly reduced the risk of neonatal sepsis (43). Two subsequent RCTs in India using BCG-Russia found no benefit among extreme LBW children (<2.000 kg) (44). This may relate to strain of BCG, as several studies have found the BCG-Denmark is much better in inducing a BCG-scar but also provide more adverse events than BCG-Russia (45).…”

Section: Non-specific Effects Of Bcg Vaccinementioning

confidence: 99%

“…Since BCG is often delayed, the median age of vaccination being more than one month in Africa (80), providing BCG vaccination within the first days of life consistently would probably reduce mortality very considerably. The relative benefit of different strains of BCG should be determined (41,44). It should be examined how the negative effects of DTP can be reduced, possibly through coadministration with BCG (72).…”

Section: Implications and Conclusionmentioning

confidence: 99%

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Developing the concept of beneficial non-specific effect of live vaccines with epidemiological studies

Aaby

Benn

2019

Clinical Microbiology and Infection

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Background and objectives Epidemiological and immunological studies are increasingly reporting non-specific effects (NSEs) of vaccines; i.e. vaccines may affect the risk and severity of non-targeted infections. We reviewed how epidemiological studies developed the concept of beneficial NSEs of live vaccines. Sources This is a personal narrative of how we came to pursue the concept of NSEs in studies of measles vaccine (MV) from the late 1970s. We also searched Pubmed for epidemiological studies of non-specific/nonspecific effects (NSEs) of the most common human vaccines. Content When smallpox vaccine was introduced around 1800, BCG against tuberculosis in the 1920s and oral polio vaccine (OPV) in the 1960s, there were suggestions that these live attenuated vaccines reduced mortality more than expected. However, scientific follow-up was limited and the concept of beneficial NSEs did not become mainstream. We observed beneficial NSEs after MV was introduced in low-income countries in the 1970s. Subsequent observational studies and randomised trials confirmed beneficial NSEs of smallpox vaccine, BCG and OPV. Recently, beneficial NSEs have been claimed for the non-live diphtheria-tetanus-pertussis and rabies vaccines. However, no non-live vaccine has yet been documented to produce beneficial NSEs. Implications Observational and experimental research has shown beneficial NSEs of four live attenuated vaccines, smallpox vaccine, BCG, OPV and MV. With immunological evidence now supporting the epidemiological observations, it is urgent to take both the specific and NSEs into account in the planning of vaccination programs.

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Section: Implications and Conclusionmentioning

confidence: 99%

Section: Non-specific Effects Of Bcg Vaccinementioning

confidence: 99%

Section: Implications and Conclusionmentioning

confidence: 99%

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Developing the concept of beneficial non-specific effect of live vaccines with epidemiological studies

Aaby

Benn

2019

Clinical Microbiology and Infection

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“…Most studies assessing the effect of BCG on all-cause mortality compared BCG-vaccinated children with unvaccinated children6 23 24 and randomised trials of BCG-Denmark have found beneficial effects in the neonatal period 8. It should be noted that two recent trials testing the effect of BCG-Russia in India found no effect;25 the different results may be related to different BCG strains 25 26. A previous study from the 1990s in Guinea-Bissau found that BCG was associated with stronger beneficial effects if provided in the first week of life 27.…”

Section: Discussionmentioning

confidence: 99%

Neonatal BCG vaccination and child survival in TB-exposed and TB-unexposed children: a prospective cohort study

et al. 2020

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ObjectivesTo assess the association between neonatal BCG vaccination and mortality between 28 days and 3 years of age among tuberculosis (TB)-exposed and TB-unexposed children.DesignProspective cohort study.SettingBandim Health Project runs an urban Health and Demographic Surveillance site in Guinea-Bissau with registration of mortality, vaccination status and TB cases.ParticipantsChildren entered the analysis when their vaccination card was inspected after 28 days of age and remained under surveillance to 3 years of age. Children residing in the same house as a TB case were classified as TB-exposed from 3 months prior to case registration to the end of follow-up.MethodsUsing Cox-proportional hazards models with age as underlying time scale, we compared mortality of children with and without neonatal BCG between October 2003 and September 2017.Main outcome measureHR for neonatal BCG compared with no neonatal BCG by TB-exposure status.ResultsAmong the 39 421 children who entered the analyses, 3022 (8%) had observation time as TB-exposed. In total, 84% of children received neonatal BCG. Children with neonatal BCG had lower mortality both in TB-exposed (adjusted HR: 0.57 (0.26 to 1.27)) and in TB-unexposed children (HR: 0.57 (95% CI 0.47 to 0.69)) than children without neonatal BCG. Children exposed to TB had higher mortality than TB-unexposed children if they had not received neonatal BCG.ConclusionNeonatal BCG vaccination was associated with lower mortality among both TB-exposed and TB-unexposed children, consistent with neonatal BCG vaccination having beneficial non-specific effects. Interventions to increase timely BCG vaccination are urgently warranted.

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“…The beneficial NSEs of BCG are of variable magnitude 4 38. A number of potential explanations are in play, including differences in BCG strain,39–41 batch variation strains,42 the enhancing effect of parental priming with BCG,43 44 genetic polymorphisms45 46 and different underlying aetiologies of neonatal disease and death.…”

Section: Discussionmentioning

confidence: 99%

Seasonal variation in the non-specific effects of BCG vaccination on neonatal mortality: three randomised controlled trials in Guinea-Bissau

et al. 2020

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The BCG vaccine protects non-specifically against other diseases than tuberculosis. Three randomised controlled trials of early BCG in Guinea-Bissau found a 38% reduction in all-cause neonatal mortality. Little is known about the underlying mechanisms. In Guinea-Bissau, prevalent infectious diseases display distinct seasonality. Revisiting the three trials (>6500 infants) comparing early BCG versus no early BCG in low weight infants on all-cause neonatal mortality over 12 consecutive years, we explored the seasonal variation in BCG’s effect on mortality. In a subgroup of participants, adaptive and innate cytokine responses were measured 4 weeks after randomisation. Consistently over the course of the three trials and 12 years, the effect of BCG on all-cause neonatal mortality was particularly beneficial when administered in November to January, coincident with peaking malaria infections. During these months, BCG was also associated with stronger proinflammatory responses to heterologous challenge. Recent studies have suggested a protective effect of BCG against malaria. BCG may also ameliorate immune-compromising fatal effects of placental malaria in the newborn.

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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

Cited by 50 publications

References 81 publications

Developing the concept of beneficial non-specific effect of live vaccines with epidemiological studies

Developing the concept of beneficial non-specific effect of live vaccines with epidemiological studies

Neonatal BCG vaccination and child survival in TB-exposed and TB-unexposed children: a prospective cohort study

Seasonal variation in the non-specific effects of BCG vaccination on neonatal mortality: three randomised controlled trials in Guinea-Bissau

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