Effective vaccination of newborns: Getting closer to the dream

In many parts of the world, babies have just one chance to be vaccinated: when they’re born. Unfortunately, newborns’ young immune systems don’t respond well to most vaccines. That’s why, in the U.S., most immunizations start at two months of age.

Currently, only BCG, polio vaccine and hepatitis B vaccines work in newborns, and the last two require multiple doses. But new research raises the possibility of one-shot vaccinations at birth — with huge implications for reducing infant mortality.

The trick? Specially designed additives — adjuvants — tailored to stimulate newborns’ unique immune systems. Two papers published today demonstrate strong vaccine responses in newborn mice — and, more importantly, in newborn monkeys, the ultimate preclinical test. Both studies used formulations designed to maximize safety.

“Our efforts have led to adjuvant approaches that may enable earlier protection of newborns and young infants from life-threatening infectious diseases, such as pneumococcus, pertussis or even respiratory syncytial virus,” says Ofer Levy, MD, PhD, who directs the Precision Vaccines Program at Boston Children’s Hospital.

Dramatic antibody response to newborn vaccines

The first of the new studies, led by David Dowling, PhD, in Boston Children’s Division of Infectious Diseases, tested an adjuvant called 3M-052. The compound works by stimulating two specific TLRs, TLR7 and TLR8. Newborn Rhesus monkeys received a series of three shots with the existing Prevnar 13 pneumococcal vaccine — “the same as my children got,” says Levy.

The team chose pneumococcal vaccine as a test case because Streptococcus pnumoniae can cause potentially fatal pneumonia, meningitis and sepsis in infants. Prevnar 13 already comes with an adjuvant, Alum, but half the monkeys were randomized to also receive 3M-052. All were monitored at the Tulane National Primate Research Center. As reported in Journal of Clinical Investigation-Insight, the immune response was dramatic.

newborn vaccines - antibody titers in Rhesus monkeys
For all 13 vaccine serotypes, levels of anti-pneumococcal antibodies (shown in red) increased much faster and much more dramatically in newborn rhesus monkeys that had 3M-052 added to their Prevnar 13 vaccine as compared with those receiving Prevnar 13 alone (in blue). Note that the scale is logarithmic. The straight dotted lines indicate minimum antibody levels needed for protection. The horizontal axis represents days from vaccination. (Click to enlarge)

At day 28, even before their second dose, the monkeys receiving 3M-052 were producing robust quantities of antibodies (see graphs above). In fact, their antibody levels were 10 to 100 times higher than those with Prevnar 13 alone — high enough to ensure protection against infection. They also showed dramatically enhanced production of CD4+ T cells and B cells specific to Streptococcus pneumoniae.

“The protective antibody response we saw was so strong that it’s conceivable that you could get protection with one shot,” says Levy. “This is critical because in many parts of the world, birth is the most reliable point of healthcare contact. After birth, it becomes challenging to bring children in for repeated clinic visits.”

Safety modifications

The 3M-052 adjuvant, manufactured by 3M Drug Delivery Systems, was chemically modified to minimize side effects. An added lipid “tail,” which mixes poorly with water, keeps the adjuvant from getting into the bloodstream where it could cause side effects.

“Rather than floating all over the place causing fever and chills, it stays put in the muscle and enhances the immune response to the vaccine,” says Levy.

The second study, published in the Journal of Allergy and Clinical Immunology, was led by Dowling and Evan Scott, PhD, of Northwestern University. It tested a different adjuvant — called CL075 — and a different type of formulation. This time, vaccine and adjuvant were encapsulated in nanoparticles designed to maximize the immune response while avoiding side effects. Specifically, the particles were engineered to be taken up by antigen-presenting cells, which instruct lymphocyte cells to make antibodies.

When the team added the particles to human cells in a dish, or injected them into mice expressing the human TLR8 gene, immune responses were as good or better than those induced by the BCG vaccine. (BCG is one of the few vaccines that works in newborns.)

newborn vaccines - formulations to improve safety
Two approaches to formulating a TLR7/8 agonist to boost vaccine effectiveness in newborns.

Next steps: medicinal chemistry, eventual human trials

The team now plans to develop highly stable vaccine formulations, obtain more safety data and further characterize responses in newborns versus older infants. Levy intends to work with collaborators from around the world, via the Precision Vaccines Program, to work towards launching human trials.

“There’s not a long list of vaccines that can be given at birth, and we need better vaccine formulations against a range of early-life infectious pathogens,” says Levy. “We hope to meet these challenges.”

Jeffrey Hubbell, PhD, of École Polytechnique Fédérale de Lausanne in Switzerland (now at University of Chicago), was co-senior author on the second paper with Levy. The research was funded by the Bill & Melinda Gates Foundation, the National Institutes of Health/NIAID, the European Research Council and Boston Children’s Hospital. The Levy Laboratory also received sponsored research support from 3M Drug Delivery Systems.

Read more in this press release from NIAID.

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