Before this year’s measles epidemic, many assumed the days of thousands of cases in a single year were behind us. That was thanks to a simple policy change in 1989: Give children two doses of the measles-mumps-rubella vaccine instead of one.
Two MMR doses set up protection against the measles 99 percent of the time, while one dose only offers 95 to 98 percent effectiveness. This thin-as-hair margin can mean the difference between complete control over the virus versus a scenario where children and pregnant mothers need worry about going outside.
Why did such a simple fix work? Why do some childhood vaccines need an additional dose or a booster shot? And what can be done to make vaccines even more effective for a specific person?
A new study, published June 11 in Cell Reports, reminds us of how much the answers to those questions hinge on one thing: our personal genetics.
“The motivation of the study was to leverage information about our genetic makeup to better understand how vaccines work,” said Daniel O’Connor, a pediatric immunologist at Oxford University, who co-led the study.
By scanning the DNA of 3,600 children from the United Kingdom and the Netherlands, the team narrowed down the genetic profiles that help establish long-lasting immunity after vaccinations for two major bacterial diseases: tetanus and meningitis-causing MenC.
In the future, they can use those profiles to tailor vaccines to an individual’s needs — reducing potential side-effects and predicting in advance how many doses a person might need before they take a shot.
Tetanus and MenC remain global threats, responsible for 60,000 and 50,000 annual deaths, respectively. But they only infect dozens of people in the U.S. per year, thanks to the success of vaccination programs.
The vaccines for these conditions, however, require booster shots to maintain effectiveness. For example, if you give a MenC vaccine to a group of infants, only half will have protective immunity by the time they turn 1.
The fact that single-course vaccines don’t always create invincibility against infection may sound like validation to the anti-vaccine crowd — who challenge the worthiness of immunizations. The current measles outbreak, which stands poised to reach heights not seen since the 1980s, is due largely to the fact that parents in some communities are refusing any dose.
But waning immunity or non-responses after a vaccine aren’t so much due to the shots, but rather the arms they’re going into.
What the study did
Getting an immunization shot seems simple. Spend a few seconds with a needle and you’re done. But the immune system is a constantly shifting war machine — with hundreds of squadrons.
When a vaccine arrives, those squads kick into gear to coordinate the body’s response. Though O’Connor said a multitude of genetic variants are likely having small individual influences, they work together to shape the way that we respond to vaccines.
Their study shows how our responses to vaccines are genetically determined — by using a genome-wide association study, or GWAS. A GWAS scans the DNA of hundreds or thousands of individuals, looking for common patterns that correspond with our health.
For this study, the health metric was antibody levels. Antibodies are the tell-tale sign that our body has built an immune defense against a pathogen invader.
By screening kids five years after their childhood immunizations, O’Connor and his team could pick out which children responded to their vaccines and which didn’t, because their antibody levels would either be high or low.
What the study found
In the case of the tetanus vaccine, the researchers found the key to building antibodies depended on genes in a family called HLA (human leukocyte antigen). When a cell gets invaded by a bacteria or virus, the HLA family carries bits of those invaders to the cell’s surface, so the infection can be detected by the immune system.
Given that bacteria and viruses are a diverse bunch, the HLA family must also carry a lot of variation, so its members can spot all the different dangers out in the world.
The team found a specific pattern — known as a single nucleotide polymorphism or SNP — that helps decide if the HLA family members get called into duty. This SNP pattern was more common in — or was associated with — people who developed persistent immunity against tetanus after vaccination, O’Connor said. HLA plays a central role in immunity, so this revelation did not come as a huge surprise.
But in the case of meningitis-causing MenC, the team identified a pair of wild cards — two portions of DNA that act like switches for signal-regulatory proteins (or SIRPs).
We now know these DNA portions play some role with vaccines, but “it hasn’t been fully described exactly what the function of these genes would be in terms of determining how we respond,” O’Connor said.
O’Connor’s study has helped identify two strong contenders in the journey to build long-lasting immunity after vaccination. But “there is quite a lot more work to be done to actually describe how these particular gene [areas] are influencing childhood vaccine responses,” he said.
Why it matters
Being able to isolate these unexpected genetic patterns speaks to the power of genome-wide association studies, which rely on big data and lots of computers to locate hidden and multifaceted connections between our health and our genetic traits.
“My labs have been working on these issues for about 30 years now,” said Gregory Poland, an immunogeneticist at the Mayo Clinic, who wasn’t involved in the study. “We thought we’d have all the answers before now,” he said. But figuring out why vaccines work in some people and fail in others “is a more complicated business than we initially thought.”
Poland said this new study falls under the field of vaccinomics, which is like a personalized medicine approach to vaccines. Vaccinomicists are searching for what factors determine whether a vaccine builds immunity as intended, fails to build immunity or — in the extremely rare case — causes an adverse reaction.
“The idea behind vaccinomics is that immune responses have tremendous inter-individual variability,” Poland said. “But these responses are not random, and if something is non-random, then it is predictable.”
Stated differently, if scientists like Poland and O’Connor can tease apart all the various ways our immune systems might respond, then they could create tailor-made vaccines. The blueprints for these custom vaccines hinge upon knowing and logging the millions of differences between our genetic codes.
“Some of the experiments I run generate a terabyte of data,” Poland said. “I cannot actually visualize my data. It’s too complex.”
And yet similarities do exist in these blueprints.
For example, research by Poland’s group shows that HLA genes also appear to play an important role in how our bodies respond to the measles vaccine. Poland said about 20 percent of the blueprint for predicting responses to the measles vaccine has been mapped out. In other cases, such as influenza, these blueprints are ready to be used today to improve vaccines and better tailor them to our genetic profiles.
“Right now, we have seven or eight different forms — dosages or preparations — of influenza vaccine. So I can pretty much choose the right vaccine for the right patient,” Poland said. “Now I couldn’t do that in the whole beginning of my career. Back then, we had one kind of influenza vaccine.”
Such work can also help researchers find vaccines for diseases such as HIV, Hepatitis C, tuberculosis — complex hypervariable pathogens, according to Poland — that still harm so many in the absence of effective, widespread immunization.
But before personalized vaccines can fill our doctor’s offices, Poland says the price of sequencing a person’s genome — or genotyping — will need to drop. That’s happening expeditiously, with price dropping from $10 million in 2007 to less than $200 in 2018. He envisions a day when the cost of genotyping will be cheaper than the cost of a vaccine.
At that point, it will make more sense to genetically screen how a person may respond to a vaccine before giving them a shot. The result will be knowing whether a person only needs one MMR shot…or two…or maybe a slightly tweaked version of the vaccine we have now to get the best outcome.