Effective one-shot vaccination of newborns moves closer to reality

March 23, 2017
For all 13 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 horizontal axis represents days from vaccination. Credit: Boston Children's Hospital

Newborns are highly vulnerable to infections and don't respond optimally to most vaccines because their young immune systems typically mount weak antibody responses. 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. In two simultaneous papers, they also describe improved adjuvant formulations that could reduce side effects.

Globally, vaccines that could be given at birth could sharply reduce infant mortality. However, currently, only BCG, polio vaccine and hepatitis B vaccines are effective in newborns, and the latter two require multiple doses for protection. 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 published March 23, in the Journal of Clinical Investigation-Insight (JCI-Insight) and the Journal of Allergy and Clinical Immunology (JACI).

"Our efforts to understand the biology of the newborn immune system has now 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 (RSV)," says Levy, director of the Precision Vaccines Program in Boston Children's Hospital's Division of Infectious Diseases and senior investigator on both studies.

Dramatic antibody response

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 randomized to also receive an adjuvant called 3M-052 that Levy, Dowling, and colleagues have shown to activate newborn immune responses. Blood was drawn at different time points to see how well the immune system was responding.

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 known as Toll-like receptors (TLRs). 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 newborns' 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.

Safety modifications

The 3M-052 adjuvant used for this monkey study, manufactured by 3M Drug Delivery Systems, is designed to minimize side effects: it is configured chemically with a lipid "tail" that mixes poorly with water. This keeps it from getting into the bloodstream, where it could cause inflammation and flu-like symptoms.

"Rather than floating all over the place causing fever and chills, when you inject this 3M-052 adjuvant, it stays put in the muscle and enhances the to the vaccine," says Levy.

The second study, co-led by Jeffrey Hubbell, PhD of École Polytechnique Fédérale de Lausanne in Switzerland (now at University of Chicago), used a different adjuvant approach described in the JACI paper. To both maximize immune and avoid systemic inflammation, the researchers encapsulated the vaccine antigen and a TLR8-activating adjuvant named CLO75 in nanoparticles. The particles were specially engineered to be taken up by antigen-presenting cells, which instruct lymphocyte cells to make antibodies.

When added to human cells in a dish and when injected into mice that express the human TLR8 gene, the nanoparticles stimulated immune responses that were as good or better than those induced by the BCG vaccine—one of the few vaccines that works in newborns.

The 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. 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 formulations against a range of early life infectious pathogens," says Levy. "We hope to meet these challenges."

Explore further: An advance for a newborn vaccine approach

Related Stories

An advance for a newborn vaccine approach

April 13, 2011
(PhysOrg.com) -- Infectious disease is a huge cause of death globally, and is a particular threat to newborns whose immune systems respond poorly to most vaccines. A new approach developed at Children's Hospital Boston, using ...

A vaccine that works in newborns? Promising compound may help protect babies during vulnerable window

March 4, 2013
The underdeveloped immune systems of newborns don't respond to most vaccines, leaving them at high risk for infections like rotavirus, pertussis (whooping cough) and pneumococcus. Researchers at Boston Children's Hospital ...

Team uncovers cellular responses to bird flu vaccine

January 20, 2017
New research from Vanderbilt eavesdrops on gene expression in human immune system cells before and after vaccination against bird flu.

Adjuvants improve immune response to H7N9 flu vaccine

July 21, 2015
In a phase 2 trial that included nearly 1,000 adults, the AS03 and MF59 adjuvants (a component that improves immune response of inactivated influenza vaccines) increased the immune responses to two doses of an inactivated ...

Infant-friendly flu vaccine developed with key protein

January 19, 2016
According to the World Health Organization, influenza causes serious illness among millions of people each year, resulting in 250,000 to 500,000 deaths. Those most at risk include infants younger than six months, because ...

Recommended for you

Exposure to larger air particles linked to increased risk of asthma in children

December 15, 2017
Researchers at The Johns Hopkins University report statistical evidence that children exposed to airborne coarse particulate matter—a mix of dust, sand and non-exhaust tailpipe emissions, such as tire rubber—are more ...

Bioengineers imagine the future of vaccines and immunotherapy

December 14, 2017
In the not-too-distant future, nanoparticles delivered to a cancer patient's immune cells might teach the cells to destroy tumors. A flu vaccine might look and feel like applying a small, round Band-Aid to your skin.

Immune cells turn back time to achieve memory

December 13, 2017
Memory T cells earn their name by embodying the memory of the immune system - they help the body remember what infections or vaccines someone has been exposed to. But to become memory T cells, the cells go backwards in time, ...

Steroid study sheds light on long term side effects of medicines

December 13, 2017
Fresh insights into key hormones found in commonly prescribed medicines have been discovered, providing further understanding of the medicines' side effects.

The immune cells that help tumors instead of destroying them

December 12, 2017
Lung cancer is the leading cause of cancer-associated deaths. One of the most promising ways to treat it is by immunotherapy, a strategy that turns the patient's immune system against the tumor. In the past twenty years, ...

Cancer gene plays key role in cystic fibrosis lung infections

December 12, 2017
PTEN is best known as a tumor suppressor, a type of protein that protects cells from growing uncontrollably and becoming cancerous. But according to a new study from Columbia University Medical Center (CUMC), PTEN has a second, ...

0 comments

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.