Could BCG Vaccination Induce Protective Trained Immunity for SARS-CoV-2?

Immunological memory in vertebrates is often exclusively attributed to T and B cell function. Recently it was proposed that the enhanced and sustained innate immune responses following initial infectious exposure may also afford protection against reinfection. Testing this concept of "trained immunity," we show that mice lacking functional T and B lymphocytes are protected against reinfection with Candida albicans in a monocyte-dependent manner. C. albicans and fungal cell wall β-glucans induced functional reprogramming of monocytes, leading to enhanced cytokine production in vivo and in vitro. The training required the β-glucan receptor dectin-1 and the noncanonical Raf-1 pathway. Monocyte training by β-glucans was associated with stable changes in histone trimethylation at H3K4, which suggests the involvement of epigenetic mechanisms in this phenomenon. The functional reprogramming of monocytes, reminiscent of similar NK cell properties, supports the concept of "trained immunity" and may be employed for the design of improved vaccination strategies. Copyright © 2012 Elsevier Inc. All rights reserved.

To the Editor: A small number of cases of coronavirus disease 2019 (Covid-19) have been described in children, 1,2 and our understanding of the spectrum of illness is limited. 3 We conducted a retrospective analysis involving hospitalized children in Wuhan, China. From January 7 to January 15, 2020, a total of 366 hospitalized children (≤16 years of age) were enrolled in a retrospective study of respiratory infections at three branches of Tongji Hospital, which are located 14 km to 34 km from one another in central Wuhan (Fig. S1 in the Supplementary Appendix, available with the full text of this letter at NEJM.org). The study was approved by the ethics committee of Tongji Hospital. Among the 366 children, the most frequently detected pathogens were influenza A virus (in 23 patients [6.3%]) and influenza B virus (in 20 [5.5%]). SARS-CoV-2, the virus that causes Covid-19, was detected in 6 patients (1.6%). Informed consent was obtained from the parents or guardians of the patients with Covid-19 for the publication of their clinical data. The dates of illness onset in the six patients with Covid-19 were between January 2 and January 8, 2020, and the patients were hospitalized between January 7 and January 13 (Fig. S2). Details of the study methods are provided in the Supplementary Appendix. The median age of the six patients was 3 years (range, 1 to 7) (Table 1). All six children had previously been completely healthy. Common clinical characteristics included high fever (>39°C) (in all six patients), cough (in all six), and vomiting (in four). Laboratory investigations showed that the levels of lymphocytes, white cells, and neutrophils were below the normal range in six, four, and three patients, respectively. Four of the six patients had pneumonia, as assessed radiographically, with computed tomographic scans of the chest showing typical viral pneumonia patterns (Fig. S3). One child was admitted to the pediatric intensive care unit (ICU) and received pooled immune globulin from healthy donors. All the patients were treated empirically with antiviral agents, antibiotic agents, and supportive therapies. All the patients recovered after hospitalization for a median of 7.5 days (range, 5 to 13). This study showed that Covid-19 occurred in children, causing moderate-to-severe respiratory illness, in the early phase of the SARS-CoV-2 outbreak in Wuhan and was associated with ICU admission in one patient. None of the patients or their family members had had direct exposure to Huanan Seafood Wholesale Market (the initial location to which cases of Covid-19 were linked) or to one another. It is worth mentioning that we unexpectedly found a case of Covid-19 in one patient (Patient 3) who resided outside Wuhan; this patient had illness onset on January 2, 2020. The patient and her family were residents of the Yangxin area of Huangshi and had not traveled outside the city in the month before illness onset. We have not identified the source of infection for this patient. Our findings indicate that SARS-CoV-2 infections in children were occurring early in the epidemic. 4

To quantify the efficacy of BCG vaccine against tuberculosis (TB). MEDLINE with index terms BCG vaccine, tuberculosis, and human. Experts from the Centers for Disease Control and Prevention and the World Health Organization, among others, provided lists of all known studies. A total of 1264 articles or abstracts were reviewed for details on BCG vaccination, concurrent vaccinated and unvaccinated groups, and TB outcome; 70 articles were reviewed in depth for method of vaccine allocation used to create comparable groups, equal surveillance and follow-up for recipient and concurrent control groups, and outcome measures of TB cases and/or deaths. Fourteen prospective trials and 12 case-control studies were included in the analysis. We recorded study design, age range of study population, number of patients enrolled, efficacy of vaccine, and items to assess the potential for bias in study design and diagnosis. At least two readers independently extracted data and evaluated validity. The relative risk (RR) or odds ratio (OR) of TB provided the measure of vaccine efficacy that we analyzed. The protective effect was then computed by 1-RR or 1-OR. A random-effects model estimated a weighted average RR or OR from those provided by the trials or case-control studies. In the trials, the RR of TB was 0.49 (95% confidence interval [CI], 0.34 to 0.70) for vaccine recipients compared with nonrecipients (protective effect of 51%). In the case-control studies, the OR for TB was 0.50 (95% CI, 0.39 to 0.64), or a 50% protective effect. Seven trials reporting tuberculous deaths showed a protective effect from BCG vaccine of 71% (RR, 0.29; 95% CI, 0.16 to 0.53), and five studies reporting on meningitis showed a protective effect from BCG vaccine of 64% (OR, 0.36; 95% CI, 0.18 to 0.70). Geographic latitude of the study site and study validity score explained 66% of the heterogeneity among trials in a random-effects regression model. On average, BCG vaccine significantly reduces the risk of TB by 50%. Protection is observed across many populations, study designs, and forms of TB. Age at vaccination did not enhance predictiveness of BCG efficacy. Protection against tuberculous death, meningitis, and disseminated disease is higher than for total TB cases, although this result may reflect reduced error in disease classification rather than greater BCG efficacy.