Thread by @FSBuchholzer

Fatal sepsis🧵(1/14)

Sepsis is a leading cause of death in the first months of life and nearly half of under-5 deaths occur in the neonatal period.

There are no specific vaccines available to prevent neonatal sepsis, which is caused by a wide range of bacterial agents, but

we have shown across 3 BCG vs no-BCG RCTs conducted in 🇬🇼 that the beneficial non-specific effects (#NSEvac) of at-birth BCG vaccination more than halves the risk of fatal neonatal sepsis among hospitalized newborns: academic.oup.com/jid/article-ab…
Likely immunological mechanisms (2/14)

are BCG-induced 1) emergency granulopoiesis (science.org/doi/10.1126/sc…) & 2) trained immunity (nature.com/articles/s4157…)
In a meta-analysis of 4 🇬🇼 RCTs, providing BCG at birth reduced fatal neonatal non-TB infections by 40% (11% to 60%), see Table 4: academic.oup.com/jid/article-ab… (3/14)

An 🇺🇬 RCT recently corroborated BCG’s protective effects against non-TB infections: thelancet.com/journals/lanin…

An important paper for the prevention of early-life fatal sepsis was published on🎄 day; but first a little background on how novel scientific discoveries arise: (4/14)

For measles vaccination (MV), we discovered in 🇬🇼 that MV provided in the presence of maternal measles antibody enhanced MV's beneficial #NSEvac.

In a 🇩🇰 RCT, we found that previous maternal BCG similarly strengthened BCG's offspring #NSEvac: academic.oup.com/jpids/article/… (5/14)

We therefore initiated several projects testing this hypothesis:

1st, compared to no scar, we found that children with a BCG scar had 66% (33%-83%) lower mortality if their mother also had a BCG scar but only 8% (−83%-53%) for mothers w. no scar: academic.oup.com/jpids/article/… (6/14)

And in a retrospective study, maternal BCG vaccine scars were associated with a 60% (4% to 83%) reduction in all-cause mortality up to 6 weeks of age: sciencedirect.com/science/articl…

We are now adding an important chapter to this developing story. (7/14)

As part of inclusion procedures in a previously published RCT testing different BCG strains provided at birth, academic.oup.com/cid/article/71…, our team assessed the maternal BCG scar status for 10,598 newborns; 60% of the mothers had a visible BCG scar from previous vaccination. (8/14)

As for providing neonatal BCG vs no BCG, being born to a mother with a BCG scar more than halved the risk of fatal sepsis by 6 weeks of age among admitted infants, the risk reduction being 51% (9% to 74%), when compared to if the mother had no scar. journalofinfection.com/article/S0163-… (9/14)

The protective effects against fatal sepsis were especially evident for males, for whom maternal scar was associated with a 65% (11% to 86%) reduction, when compared to no maternal scar.

Remember, all newborns had received BCG at birth as part of main trial procedures. (10/14)

The immunological pathways behind this intriguing finding is not yet known, but transmission of trained immunity and heterologous resistance to infections across generations was recently demonstrated by @katzmauski, @dominjor et al in @NatImmunol nature.com/articles/s4159… (11/14)

Unfortunately, BCG is not prioritized, as illustrated by the fact that 4289 mothers (40%) in our study had no 💉scar.

Despite the universal recommendation of BCG at birth, BCG is often delayed and @WHO-@UNICEF BCG coverage estimates are only compiled by 12 months of age. (12/14)

The background to this unfortunate situation is multifactorial and not least caused by logistic issues, but lets work together to remove known restrictive vial policies: tandfonline.com/doi/full/10.10… and other unnecessary barriers to BCG vaccination: bmcpublichealth.biomedcentral.com/articles/10.11…

(13/14)

I hope for help with retweets & contacts to policy-makers so we can together ensure that BCG is provided to more newborns as early as possible, especially in areas with high early-life mortality/morbidity and/or TB-endemic areas.

This would prevent many deaths globally. (14/14)

Tagging colleagues, researchers in the field & others potentially interested
@nelly_amenyogbe @nigeltwitt @StabellBenn @SThysen @AneFisker @adamhfinn @EgleButkeviciu1
@NetworkValidate @EPICVaccines @PT_Pelzer @TheDeJennerate @Radboud_Uni @LabSchultze @bcgassocguerin @PrecVaccines

@sailorrooscout @ToldiGergely @sabraklein1998 @TheUnion_TBLH @davidwdowdy @UnitingStreams @DrNicoleRitz @Sander_Lab @BCGAutoimmunity @PBettencortPhD @TB_NewsDaily @VaccinesToday @pash22 @j_zhill @Rymaniba @BallouxFrancois @WorldSepsisDay @BeatriceRNS @FranciscoMarty_ @onisillos

@MRC_Uganda @FaustmanLab @KatieLouFlan @j_sato @AlisonEUganda @f_borriello_87 @rjwarts @LSHTM @LSHTM_TB @NetworkValidate @SyddanskUni @davidjohnlynn @BrodinPetter @lindy2350 @telethonkids @DanishIAS @SUND_SDU @BiotechByron @fredddyfrancis @levy_o @BostonChildrens @BeateKampmann