Protecting newborns and young infants from life-threatening infectious diseases, such as pneumococcus or pertussis, is a complex challenge.
Their unique immune systems typically mount weak antibody responses to most vaccines, leaving them highly vulnerable to potentially fatal illnesses.
Now, researchers at Boston Children’s Hospital report achieving strong vaccine responses in newborn animals, including monkeys — the final preclinical model before human trials — by adding compounds known as adjuvants that boost the immune response.
The new studies, led by David Dowling, PhD, cap a decade of research in the laboratory of Ofer Levy, MD, PhD, aimed at tailoring vaccines to newborns’ unique immune systems. They were recently published in the Journal of Clinical Investigation-Insight (JCI-Insight) and the Journal of Allergy and Clinical Immunology (JACI).
Pneumococcal vaccine was used as a test case because it can cause potentially fatal pneumonia, meningitis, and sepsis in infants. In the first study (JCI-Insight), Newborn Rhesus monkeys were given a series of three shots with the existing Prevnar 13 pneumococcal vaccine.
This vaccine is already packaged with an adjuvant (Alum), but half the monkeys were randomised to also receive a toll-like receptor (TLR) 7 and 8 (TLR 7/8) agonist adjuvant called 3M-052, manufactured by 3M Drug Delivery Systems, that Levy, Dowling, and colleagues have shown to activate newborn animals’ immune responses. Blood was drawn at different time points to see how well the immune system was activated.
At day 28, even before receiving the second dose with 3M-052, the animals were much quicker to develop an antibody response, and their antibody levels were 10 to 100 times greater than that with Prevnar 13 alone — high enough to ensure protection against infection. They also showed dramatically enhanced CD4+ T cells and B cells specific to Streptococcus pneumoniae. (Monkey experiments were conducted at the Tulane National Primate Research Center.)
“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.”
The adjuvant works by stimulating a set of receptors on white blood cells known as Toll-like receptors. Research by the Levy Lab has found that stimulating two of these receptors, TLR7 and TLR8, induces the strongest antibody response.
Studying white blood cells derived from newborn animals’ umbilical cords, the researchers also saw robust T helper 1-cytokine production when given 3M-052 alone. When it was added to Prevnar 13, the response was synergistic.
“This study shows that the Toll-like receptor 7/8 agonist 3M-052 enhance neonatal primate immune responses to pneumococcal conjugate vaccine more effectively than Alum,” said Dr Mark Tomai, Head of 3M TLR and Microstructured Transdermal Systems (MTS) Business Development. “Many adjuvants are not very effective in newborns. The fact that 3M-052 was very effective in newborn monkeys shows the potential for using this adjuvant in immunizing the very young.”
The 3M-052 adjuvant used for this monkey study is designed to minimise side-effects: it is configured chemically with a lipid “tail” that mixes poorly with water which makes it insoluble in aqueous formulations. This configuration keeps it from getting into the bloodstream, where it could cause inflammation and flu-like symptoms. “Rather than distributing throughout the body, like other TLR 7/8 adjuvants, when you inject the 3M-052 adjuvant, it is retained at the injection site in the muscle and enhances the immune response to the vaccine,” says Levy.
The research team’s next steps are to develop a highly stable formulation, obtain more safety data and further characterize age-specific responses, comparing newborns versus older infants in animal studies.
Levy plans to work with collaborators from around the world, via the Precision Vaccines Program he founded last year, to work towards eventual 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.”