Once upon a time, an English country doctor forged a treatment out of cow pus. Edward Jenner squeezed fluid from a cowpox sore on a milkmaid’s hand, and with it, successfully inoculated an eight-year-old boy, protecting him from the related smallpox virus.
It was the world’s first successful vaccination and laid the foundation for modern vaccinology: researchers formulate vaccines from a dead or disabled microbe — or its virulent components — and people sigh with relief when they don’t succumb to the disease.
But investigators are now finding holes in traditional vaccine dogma. “Vaccines were developed under the assumption that one size fits all,” says Ofer Levy, MD, PhD, a physician-scientist in the Division of Infectious Diseases at Boston Children’s Hospital and director of the collaborative Precision Vaccines Program. “That you develop a vaccine and it will protect the same way whether the patient is young, middle aged or elderly; male or female; living in a city or rural environment; northern or southern hemisphere; whether given day or night; summer or winter.”
Another assumption: that a vaccine against a particular microbe will prevent infection only by that exact microbe.
“It turns out that all of that is wrong,” says Levy.
Probing innate immunity
A crop of new studies show that live vaccines — weakened relatives of the germs that cause disease — can provide broader protection than originally thought. For example, a measles vaccine and a common vaccine for tuberculosis appear to reduce the risk of other infections. At the same time, any one vaccine causes different responses in different populations under different conditions.
Getting at the variation in age, Levy’s group showed that when stimulated by vaccine components, infant blood cells deploy a different immune response than adult cells. The reason may be due to shifts in innate immunity, the body’s ancient and first-line defense against microbial predators.
This first, broad defense system is quicker than the so-called adaptive immune system, which includes antibodies and T-cells that have lasting memory when the same microbe tries to infect again. New studies by the Levy Laboratory and others show that innate immunity is more long-lasting than once thought and, when activated, can target microbes unrelated to the ones that initially tried to infect the host.
Put this all together and you have the basis for a new class of vaccine or vaccine boosters to shore up innate immunity, Levy says. Given early on, they could reduce the risk of multiple, unrelated infections.
The concept has implications for billions of people throughout the world who now fall prey to diarrhea, tuberculosis, respiratory infections and a host of other preventable and treatable illnesses. Globally, infections are the leading cause of death in newborns and young infants. Meanwhile, immunity is dampened in the elderly, who are often in hospitals and nursing homes where infections can run rampant.
“Infection is the biggest threat to babies and grandparents,” Levy says. “And vaccines are our best tool to protect them.”
Tracking vaccine responses
Vaccine development is limited by reliance on animal models that may not always predict human responses. To speed vaccine development, Levy’s team has developed several model systems based on human blood cells called monocytes that contribute to innate immune responses. Levy’s group isolates monocytes — from donors of different ages, for example — and exposes them to vaccines or to vaccine components called adjuvants, which act as immune response boosters.
In his most recent work, Levy teamed up with Hanno Steen, PhD, director of the Proteomics Center at Boston Children’s Hospital, to test three adjuvants: Alum, the adjuvant used in many licensed vaccines, a second adjuvant used with the human papillomavirus vaccine and a third that is a candidate for early life vaccines. Proteomics measurements, which catalog all the proteins made by a cell, showed that the cells from healthy adults responded differently to each adjuvant as compared to cells taken from the umbilical cords of newborns.
In essence, each adjuvant type dialed up or down a different set of biological pathways — clues to how effective the vaccine may be in preventing infections in specific age groups. Further, Levy showed that the proteins expressed by adult or newborn cell types could function as potential predictors of an adverse effect such as swelling or fever— leading to new ways to create smarter, more tolerable formulations.
Overall, modeling age-specific human immunity outside the body, coupled with big data approaches, could help developers formulate vaccines for distinct populations. It joins Levy’s previous “immune systems in a test tube” as a means to push the frontiers of vaccine development.
The Levy Lab’s models are one component of the Precision Vaccines Program, established by Boston Children’s with collaborators in The Gambia, British Columbia, Australia and elsewhere and philanthropic support from Henry and Carol Goldberg. The research teams are learning how vaccines work in different populations and working to develop new versions that optimally target the most vulnerable.
One initiative is enrolling newborn infants in The Gambia and Papua New Guinea, drawing blood before and immediately after immunization. They will use the samples for comparison studies using “big data” tools like proteomics and transcriptomics, which track RNA transcripts produced by the genes. Other Program members are studying immune responses in pregnant women and in infants born prematurely.
Indeed, we have come a long way from the days of cowpox and milkmaids.
“We are about to revolutionize how vaccines are developed,” says Levy, “such that they will be much better tailored to the populations that need to be protected. We may have vaccines that protect with one shot instead of four — and cross-protect against a whole range of infections in early life.”