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VAX January 2015

Vol. 13, No. 01 - January 2015

SPOTLIGHT:

With a full wallet, Gavi is set to expand influence and reach in immunizing the world’s poorest children

SPOTLIGHT:

Each step taken around British sculptor Katharine Dowson’s latest work, a translucent form frozen within eight crystal cubes, seems to change the look and composition of the sculpture’s surface. It’s like the glass is mutable: sometimes it is hard and opaque, sometimes fluid enough to reach through. A Window to the Future of an HIV Vaccine is a puzzle. The eight scored, polished blocks, each about the size of a biscuit tin, reflect, refract, and divide the ghostly shape etched inside: the clover-shaped protein that dots HIV’s surface known as the HIV trimer. “I’m hoping people will look at it and want to know what it’s about,” Dowson says. “And then they’ll read.”

Dowson modeled her sculpture on the precise structural details of the trimer protein obtaiK Dowson Final4ned by researchers at The Scripps Research Institute. Her sculpture is part of “The Art of Saving a Life” project, commissioned by the Bill & Melinda Gates Foundation and bringing together photography, illustration, paintings, music, and written stories to illustrate how vaccines continue to change the course of history (theartofsavingalife.com). The project started when Christine McNab, a Bangkok-based communications consultant, began working with the foundation to prepare for Gavi’s donor conference, held recently in Berlin, Germany, at which some of the art was exhibited (see Spotlight, this issue).

Dowson has worked for some time now incorporating science and anatomy themes into her artwork, including turning magnetic resonance scans of her brain and heart into printed molds and crystal sculptures. She’s connected to the GV Art Gallery in London, which specializes in science-related art, and sometimes works with another public health charity, the Wellcome Trust. While making A Window Dowson consulted many times with Imperial College of London mucosal infection and immunity professor Robin Shattock and his team of researchers, visiting the lab and going through the complex current scientific literature. With the Scripps trimer as a model, Dowson employed laser etching to cast the image of the protein inside the glass, each cube containing part of the whole. “The laser is light. In a sense the image doesn’t exist. It’s where the light has chipped the glass. It’s like a breath or memory. It’s there, but you can only see it because a third force has made it visible. That is what, for me, science is like: this crystallography that makes the trimer visible,” Dowson says. A Window to the Future of an HIV Vaccine is presented with seven of the cubes stacked together and one missing from the group. “Each block has a bit of the puzzle that all these laboratories and all these scientists are working on,” Dowson says. “And the puzzle hasn’t been solved.”

Chris Elias, chief of the Gates Foundation’s global development program, saw the exhibit in Berlin. “There’s a tremendous diversity of perspective and story,” he says, “and a sense with vaccines that this is one of the most important things we can do to save children’s lives around the world. We’ve made great progress but we’re still missing one out of every five children.”

Not far from where Annie Liebowitz’s group collective portrait of vaccine pioneers hung, children’s book illustrator Sophie Blackall had four watercolor-wash and ink images of village and city scenes in tThomas Ganterthe unknown health worker highres finalhe middle of a bustling day: children playing, laundry fluttering, men hauling carts. In each case health workers are arriving from one side of the image; bad news on the other. “We tell stories,” Blackall says, and recounts going to the Congo jungle, where she came to a village hit by measles. “The chief of the village had a two-year-old daughter. He’d carried her on foot for two days to the nearest clinic. She died in his arms. We arrived to a village in mourning.” Blackall’s work is carefree, fun, and deadly serious, all in one busy sweep of the page. “Art can transcend language,” Blackall says. “I’ve drawn myself out of many a hairy situation.”

German painter Thomas Ganter’s contribution focuses on how a single person can make a difference. Based on an image of a Nepalese health worker, Ganter’s painting The Unknown Health Worker presents a woman with no backdrop, in traditional dress, a cooler of vaccine strapped over her shoulder, and a wryly amused, beguiling expression. She seems to be saying “What, you expected something else?” or “Do you think this medicine would make it out there by itself?” Ganter is expressing respect and admiration. “I wanted to make a kind of monument to all of these health workers.”

For Elias the exhibit reflects many stories, all with a singular purpose. “It will help to get audiences that don’t normally think about vaccines to think about vaccines.” –Michael Dumiak

Michael Dumiak reports on global science, technology, and public health and is based in Berlin.

PRIMER

Why is it important for an AIDS vaccine to induce a balanced immune response?

The development of an AIDS vaccine presents a number of challenges stemming from HIV’s structure and behavior. One of those challenges is the clever way the virus attacks its prey. HIV preferentially targets and infects CD4+ T cells, so-called “helper” cells because they help facilitate and orchestrate other immune responses to viral infections—including helping to stimulate the production of antibodies (proteins that act against the virus in multiple ways), and activating another type of T cell known as CD8+ T cells that can kill cells in the body that are already infected by viruses such as HIV. By preferentially invading CD4+ T-helper cells, the virus severely hampers the immune system’s ability to fight back (see VAX April 2008 Primer on Understanding Cellular Immune Responses).

This presents a conundrum for vaccine researchers who are trying to design AIDS vaccine candidates that can induce potent, long-lasting immune responses against HIV. Ideally a vaccine would induce both antibody and T-cell responses without inducing too many T cells that could serve as additional targets for the virus and therefore potentially increase the risk of HIV infection. This requires careful selection of vaccine immunogens (non-infectious HIV fragments that are the active ingredients in the vaccine candidate) and the vectors that are used to shuttle these immunogens into human cells, where they are presented to the immune system and hopefully induce an immune response against HIV.
 
This makes designing a vaccine candidate the immunological equivalent of Goldilocks—finding one that induces immune responses that aren’t too little or too much, but just right.

Lessons learned

The value of inducing a balanced immune response is perhaps best illustrated by the 3,000-person Phase IIb trial known as STEP, which was stopped in 2007 (see VAX Oct.-Nov. 2007 Spotlight article, A STEP Back?). The candidate, MRKAd5, used a non-infectious common cold virus (adenovirus serotype 5, or Ad5) as a vector to deliver three HIV immunogens. Most licensed vaccines work by inducing antibodies but MRKad5 was designed to induce cellular immune responses. Most vaccinated participants who received the three-shot regimen developed CD4+ and CD8+ T-cell responses against HIV, but they were insufficient to protect against infection.

Subsequent data showed an unexpected trend toward more HIV infections occurring in subsets of vaccinated volunteers—mainly uncircumcised men and/or those who were previously exposed to and therefore had pre-existing immunity to the strain of Ad5 virus that was used as the vector. Two other efficacy trials involving an Ad5 vector were also halted prematurely, although for different reasons, and also showed a trend toward higher rates of HIV infection in vaccinated volunteers compared to those who received an inactive placebo (see VAX May 2013 Global Newsarticle).

Researchers still cannot say for certain why these vaccine candidates failed to work. Nor do theHIV Orange xsecty have any definitive explanations for the apparent increased infection risk among some vaccinated volunteers in these trials. One hypothesis is that the vaccine candidate may have induced an influx of CD4+ T cells at vulnerable mucosal sites, such as the rectum or vagina, where HIV transmission occurs, thereby providing the virus with more targets and increasing the risk of infection. While this hypothesis remains just that, an unproven theory, it has raised questions about which vectors induce the ideal immune responses and how important a balanced immune response may be.

In contrast, the prime-boost regimen (a canarypox vector-based vaccine candidate and a genetically engineered version of HIV’s gp120 surface protein) tested in the 16,000-volunteer RV144 trial in Thailand induced only modest CD4+ T-cell responses and weak or absent CD8+ T-cell responses, yet reduced HIV infection risk by 31.2% compared to placebo. The cellular immune responses this vaccine combination induced were sufficient enough to provide T cell help, but not sufficient enough to enhance infection rates. The modest protection afforded by this regimen is credited to antibody responses, which were unfortunately fleeting, confirming that immune responses not only have to be balanced, but also persistent.

The risk of imbalance

Two recent animal studies also illustrate why balanced immune responses could be key. A study in rhesus macaques by Emory University researchers showed that five different vector-based HIV vaccine candidates induced a proliferation of CD4+ T cells in rectal tissues—specifically those bearing a protein receptor that acts as a doorway through which HIV and its monkey equivalent, simian immunodeficiency virus (SIV), can enter and infect the cells—appeared to increase the risk of SIV infection in vaccinated animals subsequently exposed to SIV. Researchers hypothesize that the viral vector may trigger inflammation at mucosal sites and therefore result in recruitment of CD4+ T cells in response, which could make the animals more susceptible to infection.

Another study in mice by researchers at the Ragon Institute shows again that inducing only cellular immune responses can be detrimental. In this study a vaccine candidate designed solely to induce T-helper cells against a rodent-borne infection ended up causing uncontrolled inflammation, multiple organ failure, and death. Providing the mice with antibodies or CD8+ T cells to balance out the CD4+ T-cell response prevented the immune-related complications and mortality. As a practical matter, researchers would never design a vaccine that just induces CD4+ T cells, but eliminating these responses is also unrealistic. What’s likely needed is just the right magnitude and quality of immune responses. A Goldilocks-like challenge indeed.