A newborn baby crying. It is swaddled in a white blanket and placed on a blue and white blanket
Credit: Jade Brookbank/Getty Images
Australian researchers have discovered that giving infants antibiotics in the first few weeks of life weakens their immune response to vaccines, possibly because of changes to certain bacteria in the gut microbiome.
Experiments in mice also revealed it was possible to restore vaccine immune response by administering Bifidobacterium species or Infloran, a probiotic already proven to be safe for use in infants.
The outcomes of this study, which is published in the journal Nature, has led to a randomised controlled trial to assess whether Infloran also improves the immune response to vaccination in infants exposed to antibiotics in the first week of life.
Recruitment will begin in the coming months, with the trial to be carried out later this year.
Professor David Lynn, a program director at the South Australian Health and Medical research Institute (SAHMRI) and professor of systems immunology at Flinders University, who co-led the study, says there’s no need for undue concern for parents whose infants have had antibiotics early in life.
“Those antibiotics are given, in most cases, for very, very good reasons,
where the infants have a suspected serious infection in early life that could be life threatening. So [we] definitely do not want people [refusing] antibiotics in those circumstances.”
Babies are incredibly vulnerable in the very early stages of life and, as a result, Lynn says about 10% of newborns are given a prophylactic 48-hour course of antibiotics when an infection or sepsis is suspected.
“It’s important to recognise … it’s not like there is no response in those infants to the vaccine,” he clarifies.
“They all still respond quite well to the vaccine, and in many cases, are above what’s called the ‘sero protective threshold’ … a level of antibodies that are thought to be sufficient to provide protection against the infection.
“They do seem to wane quicker over time … but we would expect that most of those infants would be well protected against infection.”
The reduction highlights the importance of herd immunity, which should protect those without a sufficient antibody response.
The project brought together collaborators from a dozen institutions around Australia. It was co-led by Lynn and Professor Helen Marshall, medical director of the Vaccine Immunology Research Trials Unit (VIRTU) at the Women’s and Children’s Hospital, and followed 191 healthy babies from birth to 15 months old.
These infants either had no exposure to antibiotics; were given antibiotics directly, usually within the first week of life; or may have been exposed to antibiotics through their mothers during labour (intrapartum).
Their immunisations were administered as normal at birth and at 6 weeks old according to Australia’s National Immunisation Program.
The researchers, who were blinded to which infants belonged in what group, collected stool samples in the first and sixth week of life to profile the effects of antibiotics on the gut microbiome. They also took blood samples up to 15 months to measure vaccine antibody levels.
“The infants that were directly exposed to antibiotics had lower antibody titres against multiple different vaccine antigens,” says Lynn.
“But interestingly, we didn’t see the same effect in infants born to mums who had intrapartum antibiotics.”
The effect was strongest for the vaccine PCV13, which acts against Streptococcus pneumoniae, a serious bacterial infection.
PCV13 elicits antibodies of the immune system against polysaccharides (sugars) that coat the outside of S. pneumoniae. But according to Lynn, it is notoriously difficult to provoke an immune response to polysaccharides.
The vaccine somewhat circumvents this problem by joining polysaccharides to proteins, which the immune system is much better at recognising.
A man with short white hair, wearing a pale blue shirt and off-white linen blazer, smiles at the camera, he is standing in front of a white staircase and wall of triangular windows.
Professor David Lynn. Credit: SAHMRI
Nevertheless, Lynn says that the immune response to PCV13 is probably a bit weaker than to those of other vaccines given to infants. And their results indicate that it is being enhanced by signals coming from the gut microbiome.
Stool samples taken at 6 weeks old, within about 24 hours of vaccine administration, revealed levels of Bifidobacterium were significantly decreased in infants who had received direct antibiotics.
“We did see those effects in the first week of life in the intrapartum antibiotic-exposed infants as well, but it is like the microbiome had recovered by the time that those infants were getting their first vaccination,” explains Lynn.
Bifidobacterium is a genus of “good bacteria” which tend to dominate the gut microbiomes of healthy infants, particularly those who are breastfed, because they have the relatively unique ability to metabolise human milk oligosaccharides.
“It’s well been recognised that they play an important role in supporting a healthy immune system in early life,” says Lynn.
“We were able to show, in the clinical study, that the levels of those Bifidobacterium correlated quite strongly with the antibody titres 6 months later.
Experiments in “germ-free mice”, which have no bacteria in their guts at all, confirmed that it was the lack of Bifidobacterium causing the weakened immune response to the vaccines. Reintroducing Bifidobacterium, but not other types of bacteria, to the otherwise germ-free mice restored their immune response to PCV13.
“It seems that some vaccines have a greater dependency on bacteria in the gut microbiome than other vaccines,” says Lynn.
“We don’t fully understand all the mechanisms involved.”
The team trialled Infloran – a probiotic used in preterm infants to prevent against necrotising enterocolitis, a life-threatening gut disease – and found in mice that it also had a significantly beneficial effect.
The upcoming clinical trial, funded by the Women’s and Children’s Foundation at the Women’s and Children’s Hospital in Adelaide, will assess whether these results translate to human babies.
“Our data is suggestive that this could be beneficial, but the only way to establish that is through a properly done randomised controlled trial,” says Lynn.
“There are lots of probiotics on the market with varying degrees of quality, so we absolutely don’t want parents to take this into their own hands.”
He adds that there’s probably little benefit from giving otherwise healthy infants, who did not directly receive antibiotics in early life, probiotics.
The findings also don’t mean that antibiotics should not be given to the infants who need them in their first week of life.
Instead, Lynn suggests that there may be greater room for antibiotic stewardship in intrapartum antibiotics, which are administered for a variety of reasons during labour.
For example, mothers carrying Group B streptococcus bacteria in Australia are advised receive prophylactic antibiotics during labour.
“Perhaps more generally, we should be more careful with how much antibiotics we give infants over their first year or 2 of life,” he adds.
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