TB Announced

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A not-for-profit biotech helps energize the future of TB vaccine R&D
by Chael Needle

According to the World Health Organization, tuberculosis is the most common illness in individuals living with HIV and is the cause of one in four HIV-related deaths. While TB/HIV co-infection has made an impact, particularly in sub-Saharan Africa, TB has a devastating track record all on its own, as the second deadliest infectious disease after HIV, with almost 9 million new cases and 1.5 million deaths per year, and it comes with a unique set of challenges.

A lull in research, during the decades before TB came back on the radar in the 1990s, has only recently been re-energized. Ann Ginsberg, MD, PhD, Vice President for Scientific Affairs at Aeras, a not-for-profit product development partnership whose mission is focused on developing safe, effective and affordable TB vaccines, helped lead a committee at the NIH to develop a TB vaccine research blueprint in 1998. “The NIH had relatively recently begun putting resources into TB research in a serious way for the first time in many decades, at that point. So it was a matter of trying to stimulate people to come into TB vaccine research, to do some of the more basic, underlying research and discovery work, and to attract, hopefully, some of the private sector partners to get engaged. There really weren’t any with significant investments at that time,” she notes. “So the portfolio back in 1998 was really a blank slide. Certainly, the clinical portfolio. Whereas today there are roughly a dozen candidates in the clinic; there have been approximately fifteen over the last decade.”

The latest blueprint, published just this last year by the STOP TB Partnership, seeks to build on this new research and map out the way forward. Besides the need for a concerted and innovative research effort to come together, other challenges still need to be addressed. Multidrug-resistant (MDR) and extensively drug-resistant (XDR) strains of TB have evolved, making treatment more difficult. Much is still unknown about innate and adaptive immune responses to TB infection and how we might harness these pathways to achieve protective immunity. Additionally, an established vaccine against Mycobacterium tuberculosis (Mtb), Bacille Calmette-Guérin (BCG), exists, but it provides variable protection against pulmonary TB, which is not only the most infectious form of the disease but accounts for the vast majority of cases.

As an essential part of the solution, many have looked toward next-generation preventive vaccines, particularly with a major focus on prime-boost strategies.

Dr. Ginsberg explains that, because BCG is the most widely delivered vaccine to newborns; has shown significant efficacy in protecting very young children from severe forms of TB; and is extremely inexpensive and safe (as long as the individual is not HIV-positive), most public-health providers globally would be hesitant to forego these benefits. “Thus, the likelihood is that any new TB vaccine would be given as a boost on top of BCG [or a recombinant form of it],” she notes.

The protective effect would be enhanced and potentially longer lasting by this dual-step approach, an important consideration in the context that the disease often presents in adolescents and adults. “As the majority of the morbidity and the mortality from TB is in adults and adolescents, who develop, for the most part, pulmonary TB, and they’re the ones who are actively transmitting it to others, preventing TB infection in adolescents and adults would ultimately have the greatest public-health impact in the foreseeable future,” says Dr. Ginsberg. Young children who are infected with TB also are gravely affected but usually develop extra-pulmonary TB and do not typically transmit it to others. She notes: “A vaccine that could be given as a boost to adolescents and adults, even though they may have received BCG as infants, would have the greatest impact in the shortest time on the epidemic.”

Founded about a decade ago, Aeras seeks to innovate TB vaccine R&D in both its form and content. Aeras is a fully-integrated biotech not-for-profit organization, able to handle all the twists and turns of the pipeline—lab work, clinical trials, manufacturing, regulatory work, etc. Wherever possible, it also partners with others in the public and private sectors, and in academia, in order to maximize the benefits of the research community’s resources and expertise to catalyze and facilitate the development of vaccines.

The six TB vaccine candidates in the Aeras pipeline comprise half of all the vaccines currently in clinical development worldwide. Two candidates, MVA85A and AERAS–402/Crucell Ad35, are in Phase IIb, with a peptide-adjuvant candidate from GSK (in collaboration with Aeras) about to join them.

“The TB vaccine community is at a real turning point right now. We’re poised to make enormous progress,” says Dr. Ginsberg, who has brought to Aeras knowledge of product development gained at her time at Merck and TB research knowledge expanded by her time at the Global Alliance for TB Drug Development and the NIH. “And I say that not only because [Aeras has] a relatively robust portfolio of candidates that are moving through the development pipeline, but for the first time, in the first quarter of 2013, we’re going to have human efficacy data on what is the most advanced of those candidates [MVA85A]. No matter what they end up saying, those efficacy data will teach us an enormous amount.”

At the top of the list of research gaps are biomarkers, indicators of a disease state or of what confers protective immunity, and, thus, vaccine potency, stability, and, ultimately, efficacy. Explains Dr. Ginsberg: “One of the challenges in this field is that we don’t yet fully understand what constitutes a protective immune response [in humans] and, so, while we know the candidates in the clinic can all protect in various animal models for tuberculosis and we know they’re all immunogenic and stimulate one part or another or in some cases multiple parts of the total immune response, we don’t honestly know until we start getting these human efficacy data whether that corresponds to human protection.”

Being able to identify and measure biomarkers would allow for researchers to downsize and speed up human trials, among other boons for the R&D process. “We’ll be able to use those efficacy data to be able to identify candidate correlates of protection, which, of course, would help advance the field enormously in terms of streamlining clinical development and enabling us to triage and prioritize candidates much earlier in development than we can today—and with much fewer resources spent. Right now, we have to do large, long, complex efficacy trials with the clinical endpoint of [whether or not you can] actually prevent TB in a population before we know whether a candidate is working. It would be an enormous advance if we had something equivalent to viral load or CD4 counts, like they have in the HIV world, to tell us whether a candidate is promising or not.”

Aeras is also looking at its candidates in terms of how they might work to stop TB at various stages of the disease process—infection, primary disease, latency and reactivation “At this point we don’t know for sure for any given candidate whether it might protect best pre-infection or post-infection. Or even if some of these candidates may be very effective as adjuncts to TB treatments, to help improve treatment of active TB. So, at least some of the candidates ultimately will be studied in multiple populations to see their ability to protect, whether it’s pre-exposure, post-exposure, or as an adjunctive therapeutic,” explains Dr. Ginsberg. “Our top priority, for most of the newest candidates at this point, is to test them in adolescents and adults who are typically in the high burden areas and are already infected, looking to prevent active TB in that population. But of course we want to know that it’s safe as well in those who aren’t yet infected and we’ll look at whether it’s also efficacious in that population [in addition].”

Aeras is committed to helping the global TB research agenda to advance. Says Dr. Ginsberg: “We can pick up a project wherever it’s needed to help move it forward if it’s deserving….We want to bring the best and the brightest, and resources, whether public or private, from across the world to solve this challenge of developing better TB vaccines.”

Chael Needle interviewed Alisson Sombredero, MD, an HIVMA Minority Clinical Fellow, for the October issue.

November 2012

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