When Marina Ulanova began looking at the prevalence of a severe bacterial infection in the rural communities of northwestern Ontario, what she found surprised her. A worldwide vaccination push in the early 1990s had effectively wiped out the most virulent strain of the Haemophilus influenzae pathogen, which can cause meningitis, pneumonia and bacteremia, among other illnesses. Yet Ulanova's team at the Northern Ontario School of Medicine in Thunder Bay stumbled upon a different strain of H. influenzae that was wreaking havoc on the First Nations groups of the region (Clin. Infect. Dis. 49, 1240–1243, 2009).

Further laboratory analyses indicated a striking degree of uniformity in the genetic and phenotypic characteristics of the pathogenic bacterium (J. Med. Microbiol. 60, 384–390, 2011). “It was amazing,” says Ulanova. “They all looked like they belonged to the same clone.” Yet the cases had clearly originated independently; many of the infected individuals lived in communities so remote that they didn't have road access.

Gone native: Marina Ulanova is developing a vaccine tailored for Ontario's aboriginal communities. Credit: Mathieu Séguin, Northern Ontario School of Medicine

To Ulanova, the path forward was clear: an H. influenzae vaccine designed specifically against the bacterial strain plaguing the aboriginal communities of northern Ontario. In February, she and her collaborators announced plans to gather blood samples and measure antibody responses to pin down why people from these communities are so susceptible to the infection. They expect to have a prototype vaccine ready to test in clinical trials within a few months. Meanwhile, a similar project at her institute will focus on Helicobacter pylori, a bacterium that infects about 95% of First Nations individuals in the region, as compared to 50% worldwide, leading to elevated rates of peptic ulcers and stomach cancer.

These projects reflect the beginnings of a push to move beyond the one-product-fits-all nature of traditional vaccine design and toward a more targeted approach. Public health vaccination policies tend to consider everyone as the same, but how well a vaccine works often varies dramatically between population subgroups—and even between individuals.

“If we can predict who will and who won't respond, then we can design or reverse-engineer new vaccine candidates in a way that would be rational,” says Gregory Poland, a vaccinologist at the Mayo Clinic in Rochester, Minnesota. “People have spent decades and millions of dollars trying to solve these problems with old approaches, and it isn't working.”

A chip off the old vaccine

In the past few years, researchers have stepped up efforts to develop new approaches. In 2010, for example, the US National Institute of Allergy and Infectious Diseases launched a $100 million, five-year initiative called the Human Immunology Project Consortium that aims to assemble a database of genomic and other information to systematically characterize human immune response and use those data to predict how well individuals are likely to respond to shots. And, last year, the European Commission invested €30 million ($40 million) in Advanced Immunization Technologies, another five-year 'smart vaccine' project involving 42 research centers in 13 countries across the EU and US.

“The future is very exciting,” says Bali Pulendran, an immunologist at the Emory University School of Medicine in Atlanta and a participant in both efforts. “I'm very optimistic that these data are going to generate a whole new set of discoveries and insights.”

Yet, despite the focus on individual differences in immune responses, creating vaccines customized for individuals is probably not a practical strategy for most vaccines widely used in public health campaigns, argues Richard Kaslow, deputy chief officer for public health at the US Department of Veteran Affairs in Washington, DC. Instead, Kaslow predicts that vaccines will target specific ethnic populations, as Ulanova's team is doing, or other population subgroups such as young children and the elderly, both of which have distinct immune profiles.

Another strategy is to identify why certain vaccines do not generate a sufficient response in some people and then to create new versions that plug those holes. For instance, Poland and his colleagues identified a common genetic variation in a receptor to which the measles virus binds when it enters a cell. In November, they reported that the altered gene slashes some peoples' immune response to the measles vaccine by as much as 30%, probably by preventing that binding and the immune response it spurs (Hum. Hered. 72, 206–223, 2011). Now, he says, “we're looking for ways to circumvent that mutation.”

Designing this new generation of targeted vaccines won't be easy, though. Just because certain genes change their expression levels after vaccination doesn't mean they are directly involved in immunity—and pinning down the underlying mechanisms will require many different types of experiments. “It's still very much at a nascent stage,” says Pulendran, “but that's where the immunology is moving.”