The Goldilocks Approach to Vaccines
Last month, a study published by Louis Picker and his colleagues at Oregon Health & Sciences University generated a lot of excitement. The study tested a vaccine for SIV in monkeys already infected with the virus. After receiving the vaccine, 9 out of 16 monkeys cleared the infection. The NYTimes described it under the headline “New Hope for H.I.V. Vaccine.” This data builds on Picker's 2011 study that found 13 of 24 monkeys receiving the vaccine were protected from the virus. In a field mired in disappointment, many are excited about this unique approach to an HIV vaccine. However, Picker’s approach has the potential to influence more than HIV, it could change the way we think about vaccines.
On Tuesday, Louis Picker began his talk to a packed room at the AIDS Vaccine meeting in Barcelona, Spain with the line, “The trick to making a vaccine is to be humble and accept the fact that viruses are smarter than we are.” He wasn’t referring just to HIV. Instead he was talking about CMV, or cytomegalovirus.
CMV is very clever. A member of the herpes virus family, it’s over 200 million years old. This long evolution means that the virus has become adept in surviving within mammals. While the virus is found in roughly 45% of people, it rarely causes disease. Given its benign nature, Picker calls it “a parasite not a pathogen.” With these characteristics, perhaps it’s surprising that no one has attempted to use CMV in vaccines before now.
What makes Picker’s approach unique is not how it manipulates HIV. In fact, the parts of HIV used in his vaccine are far from exceptionable. The vaccine uses pieces of an HIV protein called gag, a group of proteins that make up the basic structure of the virus. The gag protein has been a component of many failed vaccine attempts. What makes this vaccine different is not the innards of HIV it contains but instead how these pieces are delivered.
Ineffective vehicles to deliver vaccines have hurt the HIV vaccine field. Just this past spring an HIV vaccine trial was halted because of delivery problems. The virus used in the halted trial, an adenovirus, wasn’t able to protect people from infection and may have been making those receiving it MORE susceptible to HIV. Whereas successful vaccines such as those for Polio are effective simply using either killed virus, or live, attenuated virus (a live virus that doesn’t cause disease), this approach doesn’t work for HIV. Something stronger is needed to clear HIV.
To create this something stronger, researchers have relied on viruses. Viruses are unbelievably good at stimulating the immune system, creating a horde of immune cells ready to ensnare and kill. But using viruses is tricky. After all, many cause disease. They first need to be engineered into empty shells, called vectors, capable of invading the immune system but unable to hurt their host. At the same time, we don’t want to make them so weak that they can’t engage with our immune system. They need to recognize HIV and kill it. But they shouldn’t produce such a powerful immune response that they overwhelm the body, potentially making it more vulnerable to pathogens.
So far HIV vaccines have tried poxviruses, which don’t yet seem to produce a strong enough immune response in humans. On the opposite end of the spectrum, trials using adenoviruses seem to produce immune responses that are a little too strong. If preliminary results are correct, CMV may be just right. This is why Picker calls CMV the goldilocks vector. It seems to have hit that elusive sweet spot. It stimulates the immune system just enough to recognize and kill HIV but not so much that our entire immune system becomes exhausted and gives up.
This is exciting because it opens the door to a new way of thinking about vaccines, one focused on the immune system response instead of the pathogen itself. It may pave the way to vaccination for a variety of diseases that have been difficult to target. One of these is tuberculosis. Picker has found that the CMV vector is effective at protecting monkeys from TB. He presented data from a small, ongoing study where 5 out of 7 monkeys were protected from the bacterial disease after vaccination. Picker postulates that CMV vectors may be effective in a multitude of diseases including malaria and herpes. For now, the data using SIV is by far the most impressive. Of the 96 monkeys they’ve tested, 48 have been protected using the CMV vaccine.
The first question Picker received after his talk at the AIDS Vaccine conference was the most obvious one: “Why half?” Why are only half of the monkeys protected from infection? It’s a mysterious finding that Picker doesn’t have an answer to. Picker wonders if it could be related to the pathogenicity of the virus they’re testing. The SIV they’re challenging with is SIVmac239. It's a notorious virus that replicates to levels 100x higher than its human counterpart HIV. The fact that the vaccine is effective against SIVmac239 raises hope that it may work even better in humans against HIV. Picker says, “I don’t know if it will be 50% in humans. It may be 70% or it may not work at all.” There’s simply no way to know until it’s tested in people. Picker hopes to start human trials in 2016.
While it’s always nice to see an effective vaccine, it would be even better if we understood how it works. While we know that the vaccine increases virus-specific effector memory T-cells, the powerhouses that remember HIV and kill it, it’s not clear how it mobilizes them. In the words of Picker, “There is no immune response correlated with protection.” The T cell responses themselves are unconventional, recognizing both class I and class II MHC molecules. This means that multiple cell types may be triggering the immune response. Even more confusing, this immune response appears to be the same in both protected and unprotected monkeys receiving the vaccine.
On the practical side, we don’t know if CMV vectors are safe in humans. Picker and his team have now designed a new type of CMV vector that is missing a gene needed for replication. While this CMV can still spread, its growth is much slower. This new design should keep the virus from causing disease. However, the jury is still out on whether this engineered CMV will maintain that elusive balance between stimulating the immune system not too much but not too little. It has to be just right.
See the full talk at the AIDS Vaccine 2013 meeting: