|© Bette Korber et al.|
I hope you will all forgive me if this week I'm gushing over my amazing mentor Bette Korber, as last week she shared some awesome news on Facebook:
"A landmark in my life happened yesterday, a major step in a long story. A decade ago I had an idea for making an HIV vaccine that had the potential to work globally. After a struggle (in my first 2 failed proposals, reviewers declared what I proposed was impossible), I got an internal grant from Los Alamos to develop the idea (third time's a charm). With that funding I could bring together a group of computational people to work together on expressing the idea -- a talented guy named Simon Perkins wrote amazing code to make it so, with computational design suggestions from the group, particularly my husband James Theiler. Then James, Will Fischer, Tanmoy Bhattacharya, and I put it through its paces, optimizing running conditions and devising ways to compare mosaics with natural proteins, with additional help from our friends Karina Yusim, Carla Kuiken and Bob Funkhouser. We called it a mosaic vaccine.After so many years of hard work, and with the collaboration of experimentalists at Harvard and at Duke (Drs. Haynes, Letvin, and Barouch), two weeks ago a phase I safety trial finally opened, and an HIV mosaic vaccine went into the arm of a human volunteer for the very first time. "Safety trial" means that this is just the first phase in testing the safety of the vaccine (I explained the three phases of human trials in this post). We will gather immune responses and we are hoping to see the same good results we saw in monkeys [2-5]. If all goes well, HIV mosaics are in the pipeline for 4 more human vaccine studies. I'm so excited about this study and so proud of my mentor.
When I explain to people the challenge we are facing when designing an HIV-1 vaccine, I usually make a very simplistic comparison with the flu virus. Influenza evolves from one season to the next, which is why every year we need a new flu shot. So, basically, the flu evolves into a new virus every year. Well, HIV evolves so rapidly that every person has a different virus. In our database alone we have half a million distinct HIV viral sequences: how can you vaccinate people against half a million different viruses?
In the past, successful vaccines against diseases like polio or the measles have been made by taking a real virus, inactivating it (for example, you just take one or two of its proteins, but not the whole virus, to ensure it loses its ability to infect cells), and then injecting it into the body. The immune system "sees" the viral proteins and initiates a response. The response is then "saved" into memory cells, which, next time they encounter the pathogen, will remember how to produce the right response that will promptly clear the virus before it can start an active infection.
So, as you can see, the problem with HIV is that the viral population is so diverse that no one virus found in nature will protect people from contracting the infection. How to bypass the obstacle, then? Bette's idea is to basically use a computer that mimics HIV's evolutionary mechanisms to create an in-silico virus , something I've discussed in this post. The algorithm takes as input a population of, say, 100 different HIV sequences, and then recombines them creating a new population of artificially constructed viral sequences. HIV viruses can naturally recombine when infecting the same cells, and what the algorithm does is mimic this mechanism making sure that after every recombination step the new sequence is still a viable and functional virus. The computer mimics this process, iterates it multiple times and then the best representative is selected as a potential vaccine.
The first caveat is: is this new, artificially constructed sequence a real virus? After all, it was never found in nature. It was created by a computer algorithm. It turns out that when reconstructed in a wet lab, the mosaic proteins are functional and viable.
The second hurdle was to prove that these artificially constructed sequences are safe to be used in a vaccine and that they do elicit protective responses against not just a few HIV viruses, but many, many HIV viruses -- enough to prevent infection. So, you get an idea of why the mosaic vaccine took 10 years from concept to the first human trial.
Animal studies [2-5] demonstrated that mosaic vaccines elicit good immune responses. In one study in particular , compared to controls, vaccinated monkeys required many more challenges to get infected (for a risk reduction of 80%), and once infected, they were able to control the viral load and survive the infection.
So, as Bette said, we are hopeful. Hopeful and excited!
 Fischer W, Perkins S, Theiler J, Bhattacharya T, Yusim K, Funkhouser R, Kuiken C, Haynes B, Letvin NL, Walker BD, Hahn BH, & Korber BT (2007). Polyvalent vaccines for optimal coverage of potential T-cell epitopes in global HIV-1 variants. Nature medicine, 13 (1), 100-6 PMID: 17187074
 Nkolola JP, Bricault CA, Cheung A, Shields J, Perry J, Kovacs JM, Giorgi E, van Winsen M, Apetri A, Brinkman-van der Linden EC, Chen B, Korber B, Seaman MS, & Barouch DH (2014). Characterization and immunogenicity of a novel mosaic M HIV-1 gp140 trimer. Journal of virology, 88 (17), 9538-52 PMID: 24965452
 Barouch DH, Stephenson KE, Borducchi EN, Smith K, Stanley K, McNally AG, Liu J, Abbink P, Maxfield LF, Seaman MS, Dugast AS, Alter G, Ferguson M, Li W, Earl PL, Moss B, Giorgi EE, Szinger JJ, Eller LA, Billings EA, Rao M, Tovanabutra S, Sanders-Buell E, Weijtens M, Pau MG, Schuitemaker H, Robb ML, Kim JH, Korber BT, & Michael NL (2013). Protective efficacy of a global HIV-1 mosaic vaccine against heterologous SHIV challenges in rhesus monkeys. Cell, 155 (3), 531-9 PMID: 24243013
 Santra S, Muldoon M, Watson S, Buzby A, Balachandran H, Carlson KR, Mach L, Kong WP, McKee K, Yang ZY, Rao SS, Mascola JR, Nabel GJ, Korber BT, & Letvin NL (2012). Breadth of cellular and humoral immune responses elicited in rhesus monkeys by multi-valent mosaic and consensus immunogens. Virology, 428 (2), 121-7 PMID: 22521913
 Barouch DH, O'Brien KL, Simmons NL, King SL, Abbink P, Maxfield LF, Sun YH, La Porte A, Riggs AM, Lynch DM, Clark SL, Backus K, Perry JR, Seaman MS, Carville A, Mansfield KG, Szinger JJ, Fischer W, Muldoon M, & Korber B (2010). Mosaic HIV-1 vaccines expand the breadth and depth of cellular immune responses in rhesus monkeys. Nature medicine, 16 (3), 319-23 PMID: 20173752