Vaccines can have nonspecific effects through their modulation of responses to infections not specifically targeted by the vaccine. However, lack of knowledge about the underlying immunological ...mechanisms and molecular cause-and-effect relationships prevent use of this potentially powerful early-life intervention to its greatest benefit. The World Health Organization has identified investigations into the molecular basis of nonspecific vaccine effects as a research priority.
Background. BCG vaccine may reduce overall mortality by increasing resistance to nontuberculosis infections. In 2 randomized trials in Guinea-Bissau of early BCG-Denmark (Statens Serum Institut) ...given to low-weight (LW) neonates (<2500 g at inclusion) to reduce infant mortality rates, we observed a very beneficial effect in the neonatal period. We therefore conducted the present trial to test whether early BCG-Denmark reduces neonatal mortality by 45%. We also conducted a meta-analysis of the 3 BCG-Denmark trials. Methods. In 2008–2013, we randomized LW neonates to "early BCG-Denmark" (intervention group; n = 2083) or "control" (local policy for LW and no BCG-Denmark; n = 2089) at discharge from the maternity ward or at first contact with the health center. The infants were randomized (1:1) without blinding in blocks of 24. Data was analyzed in Cox hazards models providing mortality rate ratios (MRRs). We had prespecified an analysis censoring follow-up at oral poliovirus vaccine campaigns. Results. Early administration of BCG-Denmark was associated with a nonsignificant reduction in neonatal mortality rate (MRR, 0.70; 95% confidence interval CI, .47–1.04) and a 34% reduction (0.66; .44–1.00) when censoring for oral poliovirus vaccine campaigns. There was no reduction in mortality rate for noninfectious diseases, but a 43% reduction in infectious disease mortality rate (MRR, 0.57; 95% CI, .35–.93). A meta-analysis of 3 BCG trials showed that early BCG-Denmark reduced mortality by 38% (MRR, 0.62; 95% CI, .46–.83) within the neonatal period and 16% (0.84; .71–1.00) by age 12 months. Conclusion. Early administration of BCG-Denmark in LW infants is associated with major reductions in mortality rate. It is important that all LW infants receive early BCG in areas with high neonatal mortality rates. Clinical Trials Registration. NCT00625482.
Background. Routine vaccines may have nonspecific effects on mortality. An observational study found that OPV given at birth (OPV0) was associated with increased male infant mortality. We ...investigated the effect of OPV0 on infant mortality in a randomized trial in Guinea-Bissau. Methods. A total of 7012 healthy normal-birth-weight neonates were randomized to BCG only (intervention group) or OPV0 with BCG (usual practice). All children were to receive OPV with pentavalent vaccine (diphtheria, tetanus, pertussis, Haemophilus influenzae type b, and hepatitis B) at 6, 10, and 14 weeks of age. Seven national OPV campaigns were also conducted during the trial period. Children were followed to age 12 months. We used Cox regression to calculate hazard ratios (HRs) for mortality. Results. The trial contradicted the original hypothesis about OPV0 increasing male infant mortality. Within 12 months, 73 children in the BCG + OPV group and 87 children in the BCG-only group died, all from infectious diseases. Comparing BCG + OPV0 vs BCG only, the HR was 0.83 (95% confidence interval CI, .61–1.13): 0.72 (95% CI, .47–1.10) in boys and 0.97 (95% CI, .61–1.54) in girls. For children enrolled within the first 2 days of life, the HR for BCG + OPV0 vs BCG only was 0.58 (95% CI, .38–.90). From enrollment until the time of OPV campaigns, the HR was 0.68 (95% CI, .45–1.00), the beneficial effect being separately significant for males (0.55 95% CI, .32–.95), Conclusions. This is the only randomized trial of the effect of OPV0 on mortality. OPV0 may be associated with nonspecific protection against infectious disease mortality, particularly when given early in life. There are reasons to monitor mortality when OPV is being phased out. Clinical Trials Registration. NCT00710983.
Background. Observational studies have suggested that BCG may have nonspecific beneficial effects on survival. Low-birth-weight (LBW) children are not given BCG at birth in Guinea-Bissau; we ...conducted a randomized trial of BCG at birth (early BCG) vs delayed BCG. Methods, In the period 2004—2008 we recruited 2320 LBW children in Bissau. The children were visited at home at 2, 6, and 12 months of age. With a pretrial infant mortality of 250 per 1000, we hypothesized a 25% reduction in infant mortality for LBW children. Results. Infant mortality was only 101 per 1000 during the trial. In the primary analysis, infant mortality was reduced insignificantly by 17% (mortality rate ratio MRR = .83 .63—1.08). In secondary analyses, early BCG vaccine was safe with an MRR of .49 (.21—1.15) after 3 days and .55 (.34—.89) after 4 weeks. The reduction in neonatal mortality was mainly due to fewer cases of neonatal sepsis, respiratory infection, and fever. The impact of early BCG on infant mortality was marked for children weighing < 1.5 kg (MRR = .43 .21—.85) who had lower coverage for diphtheria-tetanus-pertussis vaccinations. Conclusions. Though early BCG did not reduce infant mortality significantly, it may have a beneficial effect in the neonatal period. This could be important for public health because BCG is often delayed in low-income countries.
We have recently shown that BCG (Bacillus Calmette-Guérin) vaccination in healthy volunteers induces epigenetic reprogramming of monocytes, leading to increased cytokine production in response to ...nonrelated pathogens for up to 3 months after vaccination. This phenomenon was named ‘trained immunity'. In the present study we assessed whether BCG was able to induce long-lasting effects on both trained immunity and heterologous T helper 1 (Th1) and Th17 immune responses 1 year after vaccination. The production of TNFα and IL-1β to mycobacteria or unrelated pathogens was higher after 2 weeks and 3 months postvaccination, but these effects were less pronounced 1 year after vaccination. However, monocytes recovered 1 year after vaccination had an increased expression of pattern recognition receptors such as CD14, Toll-like receptor 4 (TLR4) and mannose receptor, and this correlated with an increase in proinflammatory cytokine production after stimulation with the TLR4 ligand lipopolysaccharide. The heterologous production of Th1 (IFN-γ) and Th17 (IL-17 and IL-22) immune responses to nonmycobacterial stimulation remained strongly elevated even 1 year after BCG vaccination. In conclusion, BCG induces sustained changes in the immune system associated with a nonspecific response to infections both at the level of innate trained immunity and at the level of heterologous Th1/Th17 responses.
It is very exceptional that a new disease becomes a true pandemic. Since its emergence in Wuhan, China, in late 2019, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus that ...causes COVID-19, has spread to nearly all countries of the world in only a few months. However, in different countries, the COVID-19 epidemic takes variable shapes and forms in how it affects communities. Until now, the insights gained on COVID-19 have been largely dominated by the COVID-19 epidemics and the lockdowns in China, Europe and the USA. But this variety of global trajectories is little described, analysed or understood. In only a few months, an enormous amount of scientific evidence on SARS-CoV-2 and COVID-19 has been uncovered (knowns). But important knowledge gaps remain (unknowns). Learning from the variety of ways the COVID-19 epidemic is unfolding across the globe can potentially contribute to solving the COVID-19 puzzle. This paper tries to make sense of this variability—by exploring the important role that context plays in these different COVID-19 epidemics; by comparing COVID-19 epidemics with other respiratory diseases, including other coronaviruses that circulate continuously; and by highlighting the critical unknowns and uncertainties that remain. These unknowns and uncertainties require a deeper understanding of the variable trajectories of COVID-19. Unravelling them will be important for discerning potential future scenarios, such as the first wave in virgin territories still untouched by COVID-19 and for future waves elsewhere.
Artificial intelligence and machine learning have become a necessary part of modern living along with the increased adoption of new computational devices. Because machine learning and artificial ...intelligence can detect malware better than traditional signature detection, the development of new and novel malware aiming to bypass detection has caused a challenge where models may experience concept drift. However, as new malware samples appear, the detection performance drops. Our work aims to discuss the performance degradation of machine learning-based malware detectors with time, also called concept drift. To achieve this goal, we develop a Python-based framework, namely Rapidrift, capable of analysing the concept drift at a more granular level. We also created two new malware datasets, TRITIUM and INFRENO, from different sources and threat profiles to conduct a deeper analysis of the concept drift problem. To test the effectiveness of Rapidrift, various fundamental methods that could reduce the effects of concept drift were experimentally explored.
WHO recommends BCG at birth and diphtheria-tetanus-pertussis (DTP)-containing vaccine at 6, 10 and 14weeks of age. However, BCG and DTP are often co-administered in low-income countries. The health ...implications have not been examined.
We reanalysed data from Matlab, Bangladesh, to examine the influence of co-administration on mortality; 37,894 children born 1986-1999 were followed with registration of vaccinations and survival.
Using Cox models, survival was analysed from 6weeks to 9months of age when measles vaccine is given; 712 children died in this age group. We calculated mortality rate ratios (MRR) for children starting the vaccination schedule with BCG-first, BCG+DTP1-first or DTP1-first.
Only 17% followed the WHO-schedule with BCG-first. Mortality was 16/1000 person-years for children who initiated the vaccination schedule with BCG+DTP1 but 32/1000 and 20/1000 for children who received BCG-first or DTP-first, respectively. Compared with BCG+DTP1-first and adjusting for background factors, the BCG-first-schedule was associated with 2-fold higher mortality (MRR=1.94 (1.42–2.63)). DTP1 administered after BCG-first was associated with higher mortality than receiving DTP1 with BCG (MRR=1.78 (1.03–3.03)).
Co-administration of BCG and DTP may further reduce mortality. Since all observational studies support this trend, co-administration of BCG and DTP should be tested in randomised trials.
•Though not recommended by WHO, BCG is often given with diphtheria-tetanus-pertussis (DTP) vaccine in low-income countries.•We reanalyzed a study of 37,894 children from Bangladesh. Most children had received BCG+DTP1 as their first vaccination.•Having received BCG-first was associated with 2-fold higher mortality than having received BCG+DTP1-first.•Co-administration of BCG and DTP vaccinations may hold potential for reducing child mortality further.
Vaccines have non-specific effects on child survival by affecting susceptibility to non-targeted infections. Live vaccines may reduce susceptibility whereas non-live vaccine may enhance susceptibility to unrelated infections. Since the most recent vaccine has the strongest effects, sequence of vaccinations may be important for child survival. WHO recommends BCG-at-birth followed by three doses of DTP at 6, 10 and 14weeks of age. However, in a large study from Bangladesh, adjusting for background factors, the WHO sequence was associated with 2-fold higher mortality than receiving BCG+DTP1-first. Hence, co-administration of BCG and DTP may hold potential to reduce child mortality further.
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