Vaccines: what is the meaning of phase I, II and III?

I'm often asked, "How long will it take to finally have an HIV vaccine? Are we close? What about this study that published good results on an HIV vaccine?"

Right now, the HIV community is generally optimistic that we will indeed have an HIV vaccine within the next decade. This is based on the relatively recent discovery of new broadly neutralizing antibodies and the mildly positive results obtained by one of the five major efficacy trials, the RV144 Thai trial, which found a 31% reduction in HIV acquisition in vaccinated subjects versus placebo [1].

I'm also often forwarded published papers on successful HIV vaccine trials, with the attached question: "Is it done, then?"

The answer is, "No, not yet."

As I explained in my earlier HPV vaccine post, once a vaccine is approved to be tested on humans, like all human health interventions, it has to be tested in three phase clinical trials, called phase I, II, and III.

"Clinical product development typically begins with phase I studies that evaluate the safety and biological activity of a drug, vaccine, or other intervention and proceeds ultimately to phase III efficacy trials that support licensure. [. . .] Phase II clinical trial evaluation affords an opportunity to discover less frequent side effects of the intervention and to provide better quantitation of the agent‚ activity and safety in a larger and more diverse participant population. [2]."

So, a successful phase I trial means that the vaccine is safe to use on humans and it does no harm. A phase I trial does not prove that the vaccine can protect against the disease. It can take up to a decade to go from a phase I to a phase III trial. Phase III, when successful, is what ultimately proves the vaccine's efficacy.

So far there have been many phase I HIV vaccine trials, but there only have been a handful phase III trials, of which the most successful one was RV144 with the mild 31% reduction in infection rate.

Vaccines like HPV that are now being offered to the public have undergone all three clinical trial phases. This is what I was trying to explain when I discussed the HPV vaccine and I said that despite the concerns raised by the Japanese government, the vaccine wouldn't have been FDA approved had it not passed all three phases of clinical trials that proved its safety first. For example, you can read the results of a phase I HPV vaccine trial here. Notice that the paper was published in 2000 and it took roughly another decade before the vaccine was distributed.

"Before the question of drug or vaccine efficacy can be answered, safety testing, validation of mechanism, and specificity issues must be addressed in preliminary studies. These studies themselves often provide unexpected information that generates new hypotheses. An efficacy trial, usually a randomized controlled trial‚ represents the ultimate test of concept that an intervention can ameliorate disease or prevent infection [2]."

Phase I and II trials are also important for hypothesis raising, not just hypothesis testing. Back to the HIV example, we still don't know why it takes so long for the human body to produce antibodies able to recognize a broad spectrum of HIV strains. We still don't know why a small percent of HIV-infected subjects, the so called "elite-controllers", are able to keep their viral load down to undetectable for decades. We still don't have biomarkers that predict the strength of an immunological response to the vaccine. People who make strong antibodies, they make them later in the infections, when it's too late to clear the virus. Elite controllers, on the other hand, have very low antibody titers.

Finally, to make things even more complicated, the animal models used to test vaccines are not good predictors of the human immune system. For examples, vaccinated macaques have been challenged with SIV, the simian immunodeficiency virus, which is a much older virus than HIV. There are ways to "humanize" the monkeys, but they can never 100% predict the human trial. And that's why we've been eagerly waiting for phase I of the mosaic vaccine... unfortunately, we are still waiting. I should have an update soon, though, as I'm heading out to see our collaborators later this week. Stay tuned!

[1] Supachai Rerks-Ngarm, et al. (2009). Vaccination with ALVAC and AIDSVAX to Prevent HIV-1 Infection in Thailand N Engl J Med DOI: 10.1783/147118910790291082

[2] Lawrence Corey, Gary J. Nabel, Carl Dieffenbach, Peter Gilbert, Barton F. Haynes, Margaret Johnston, James Kublin, H. Clifford Lane, Giuseppe Pantaleo, Louis J. Picker and Anthony S. Fauci (2011). HIV-1 Vaccines and Adaptive Trial Designs Sci Transl Med DOI: 10.1126/scitranslmed.3001863